TW200418455A - Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration - Google Patents
Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration Download PDFInfo
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- TW200418455A TW200418455A TW092130486A TW92130486A TW200418455A TW 200418455 A TW200418455 A TW 200418455A TW 092130486 A TW092130486 A TW 092130486A TW 92130486 A TW92130486 A TW 92130486A TW 200418455 A TW200418455 A TW 200418455A
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- cytokine inhibitory
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Abstract
Description
200418455 玖、發明說明: 本申請案主張2002年10月31日申請之美國臨時申請案號 60/422,900之權益,其内容已以引用之方式完全併入本文中。 【發明所屬之技術領域】 本發明係有關治療、預防與處理黃斑變性(MD)及相關症 候群之方法,其包括投予選擇性細胞激素抑制性藥劑,可 單獨投藥或併用已知療法。本發明亦有關醫藥組合物與投 藥療程。特定言之,本發明包括以選擇性細胞激素抑制性 藥劑併用手術干預與/或黃斑變性之其他標準療法之用法。 【先前技術】 黃斑變性之病理學 黃斑變性(MD)為一種經由傷害黃斑而破壞中心視覺之眼 睛疾病。黃斑為視網膜之一部份,為一層主要位在眼球内 部之薄層神經細胞。視網膜中之神經細胞會檢測光線,送 至腦訊號,告訴腦部眼睛看到了什麼。黃斑接近眼球後方 之視網膜中心,動物用於聚焦在其面前之事物,得到清楚 之中心影像。視網膜之其餘部份提供側面(周邊)影像。 MD有兩種型式:萎縮(“乾型”)與滲出(“濕型”)。Riordan-Eva, P·,Eye,in Current Medical Diagnosis and Treatment,41 ed. 210-211 (2002)。90%患者為乾型,僅10%為濕型。然而,濕 型患者中有高達90%可能失明。DuBosar,R·,J. of Ophthalmic Nursing and Technology,18: 60-64 (1998) 〇 黃斑變性造成有脈絡膜小疣之眼中出現脈絡膜新血管形 成(CNVM)與/或視網膜色素上皮(RPE)幾何性萎縮。Bird, 89179 200418455 A.C·,Surv. Ophthamol. 39:367-74 (1995)。脈絡膜小疲為位在神 經視網膜外之基底中之圓形白·黃色小點。MD之其他症狀包 括RPE剥離(PED)與黃斑下之盤狀結疤組織。Algvere,P_V., Acta Ophthalmologica Scandinavica 80:136-143 (2002)。 脈絡膜新血管形成為一種與多種視網膜疾病有關之問 題,但主要仍與MD有關。CNVM之特徵為自脈絡膜(緊臨視 網膜下方之富含血管組織層)長出異常血管,延伸至視網膜 層。此等新血管極為脆弱,容易破裂,造成血液與體液流 至視網膜層中。當血管滲漏時,即會干擾精密之視網膜組 織,造成視力受損。其症狀之嚴重性依CNVM大小及其接近 黃斑之程度而定。患者之症狀可能非常溫和,如:視力模 糊或視野扭曲或更嚴重,如··中心盲點。 出現脈絡膜小疣且可能出現色素異常但沒有CNVM或幾 何性萎縮之患者通常診斷為與老化有關之黃斑變性 (ARM)。參見上述文獻。ARM與MD之組織病理學特徵為在 RPE細胞基底之布魯赫膜(Bruch’s membrane)内部連續沉積一 層細粒物質。Sarks,J.P·,et al·,Eye 2(Pt. 5):552-77 (1988)。此 等基底沉積物被認為是連續RPE呑噬作用或光受體外層物 質產生之廢物累積結果。基底沉積物造成布魯赫膜增厚及 通透性降低。有假說認為,水通透性下降會損害營養素交 換、聚積水分及促進發展出軟的脈絡膜小疣與PED,最後造 成RPE細胞萎縮。參見上述文獻。然而,目前對ARM與MD 病理學之整體了解並不完全,Cour,M·,et al·,Drugs Aging 19:101-133 (2002)。 89179 200418455 由於MD好發於老年,此族群成長快速,因此MD成為重 大經濟與社會問題。黃斑為發展中國家60歲以上人口喪失 視力之最常見原因。黃斑變性使170萬名美國人喪失視力, 其他1100萬人處於危險狀態。DuBosar,R·,J· of Ophthalmic Nursing and Technology,18: 60-64 (1998)。目前尚無已知之治 療法。Rhoodhooft,J·,Bull· Soc. beige Ophtalmol. 276:83-92 (2000)。因此,急需一種有效治療MD之方法。 與老化相關之黃斑變性之治療法 直到目前為止,雷射光致凝結法為例行用於MD之唯一治 療法,其僅提供中度治療效果。雷射光致凝結法為一種雷 射手術,其利用集中光束燒灼小區域之視網膜及黃斑下方 之異常血管。燒灼造成結症組織,密封血管,保持黃斑下 方免於滲漏。雷射光致凝結法僅對患有濕型MD之患者有 效。此外,雷射光致凝結法僅可供彼等患者中約13%選擇使 用。Joffe,L.等人,International Ophthalmology Clinics 36(2): 99-116 (1996)。雷射光致凝結法無法治癒濕型MD,但有時候 會減緩或防止中心視力喪失。然而,若不加治療,因濕型 MD喪失之視力將會持續發展至患者之殘餘視力均喪失。 雷射手術之最嚴重缺點為雷射會傷害黃斑中一些會與光 反應之神經細胞,導致一些視力喪失。有時候,因手術造 成之視力喪失如同未處理時造成之視力喪失程度或更嚴 重。然而有些患者接受雷射手術後初期之視力變差,但可 防止視力隨時間惡化。 菲特芬(Verteporfin)近來已用於治療濕型MD。Cour,M·,等 89179 200418455 人,Drugs Aging 19:101-133 (2002)。菲特芬為一種血管阻斷 性光反應性染料,係經由注射投藥。染料會移向造成視力 喪失之血管,然後在氧之存在下被一道進入眼睛之非燒灼 性閃光活化。菲特芬主要經由脂蛋白送入血漿中。活化之 菲特芬產生極具反應性之短壽命之單一氧與反應性氧自由 基,造成新生血管内皮之局部傷害。結果造成血管閉塞。 已知受傷之内皮會透過脂質-氧化酶(白三烯)與環氧化酶 (類花生酸如:前列凝素)途徑釋出凝血劑原及血管活性因 子,造成血小板凝結、形成血纖維蛋白凝塊及血管收縮。 菲特芬似乎傾向累積在新生血管中,包括脈絡膜新生血 管。然而,動物模式顯示,菲特芬亦會累積在視網膜中。 因此,投予菲特芬可能連帶傷害視網膜結構,包括視網膜 色素上皮與視網膜之外核層。 目前用於治療MD之另一種方法為藥物性抗血管擴增療 法。Cour,M·,等人,Drugs Aging 19:101-133 (2002)。然而,第 一種採用抗血管擴增劑:干擾素-α之臨床試驗無法有效治 療 MD,產生高度副作用。Arch. Ophthalmol. 115:865-72 (1997)。 玻璃體内注射去炎松(triamcinolone)據稱可在猴子體内抑 制雷射所謗發之CNVM,但無法在隨機試驗中阻止MD患者 在一年内嚴重喪失視力。Gillies,M.C·,等人,Invest. Ophthalmol Vis. Sci. 42:S522 (2001)。許多其他抗血管擴增藥物已達供MD 患者使用之不同發展階段,包括血管抑制性類固醇(例如: 安克塔乙酸鹽(anecortave acetate),Alcon藥廄)及血管上皮生 長因子(VEGF)抗體或其片段。Guyer,D.R·,等人,Invest. 89179 200418455200418455 发明 Description of the Invention: This application claims the benefit of US Provisional Application No. 60 / 422,900, filed on October 31, 2002, the contents of which have been fully incorporated herein by reference. [Technical field to which the invention belongs] The present invention relates to a method for treating, preventing and treating macular degeneration (MD) and related syndromes, which comprises administering a selective cytokine inhibitory agent, which can be administered alone or in combination with known therapies. The invention also relates to pharmaceutical compositions and medications. In particular, the invention includes the use of selective cytokine inhibitory agents in combination with surgical intervention and / or other standard therapies for macular degeneration. [Previous Technology] Macular Degeneration Pathology Macular Degeneration (MD) is an eye disease that damages central vision by harming the macula. The macula is part of the retina and is a thin layer of nerve cells located mainly inside the eyeball. The nerve cells in the retina detect the light and send it to the brain to tell the brain what the eyes see. The macula is close to the center of the retina behind the eyeball, and the animal uses it to focus on the things in front of it to get a clear central image. The rest of the retina provides side (peripheral) images. There are two types of MD: atrophy ("dry") and exudate ("wet"). Riordan-Eva, P., Eye, in Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). Ninety percent of patients are dry and only 10% are wet. However, up to 90% of wet patients may be blind. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18: 60-64 (1998). Macular degeneration causes choroidal neovascularization (CNVM) and / or retinal pigment epithelium (RPE) geometry in eyes with choroidal warts. Shrink. Bird, 89179 200418455 A.C., Surv. Ophthamol. 39: 367-74 (1995). Choroidal fatigue is small round white and yellow dots in the basal area outside the retina. Other symptoms of MD include detachment of RPE (PED) and discoid scar tissue under the macula. Algvere, P.V., Acta Ophthalmologica Scandinavica 80: 136-143 (2002). Choroidal neovascularization is a problem related to many retinal diseases, but it is still mainly related to MD. CNVM is characterized by abnormal blood vessels growing from the choroid (the vascular-rich tissue layer immediately below the visual omentum) and extending to the retinal layer. These new blood vessels are extremely fragile and easily ruptured, causing blood and body fluids to flow into the retinal layer. When a blood vessel leaks, it can interfere with delicate retinal tissue and cause vision damage. The severity of the symptoms depends on the size of the CNVM and how close it is to the macula. The patient's symptoms may be very mild, such as blurred vision or distorted vision or more severe, such as central blind spots. Patients with choroid warts and possibly pigmented abnormalities but without CNVM or geometric atrophy are usually diagnosed with age-related macular degeneration (ARM). See above. The histopathology of ARM and MD is characterized by the continuous deposition of a layer of fine-grained material inside the Bruch's membrane at the base of RPE cells. Sarks, J.P., et al., Eye 2 (Pt. 5): 552-77 (1988). These basal deposits are considered to be the result of continuous RPE phagocytosis or accumulation of waste from the outer layers of photoreceptors. Basement deposits result in thicker Bruch membranes and reduced permeability. There is a hypothesis that a decrease in water permeability will impair nutrient exchange, accumulate water, and promote the development of soft choroid warts and PED, and eventually cause RPE cells to shrink. See above. However, the current overall understanding of ARM and MD pathology is incomplete, Cour, M., et al., Drugs Aging 19: 101-133 (2002). 89179 200418455 Because MD occurs in old age and this group grows rapidly, MD has become a major economic and social issue. Macularity is the most common cause of vision loss in people over 60 in developing countries. Macular degeneration has caused 1.7 million Americans to lose sight and 11 million others to be at risk. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18: 60-64 (1998). There is no known cure. Rhoodhooft, J., Bull. Soc. Beige Ophtalmol. 276: 83-92 (2000). Therefore, there is an urgent need for an effective method for treating MD. Treatments for age-related macular degeneration Until now, laser-induced coagulation has been the only treatment routinely used for MD, which only provides a moderate therapeutic effect. Laser photocoagulation is a type of laser surgery that uses a focused beam to burn small areas of the retina and abnormal blood vessels beneath the macula. Cautery causes infectious tissue, seals blood vessels, and prevents the macula from leaking. Laser photocoagulation is effective only in patients with wet MD. In addition, laser photocoagulation is only available to about 13% of their patients. Joffe, L. et al. International Ophthalmology Clinics 36 (2): 99-116 (1996). Laser photocoagulation does not cure wet MD, but it sometimes slows or prevents central vision loss. However, without treatment, vision loss due to wet MD will continue to develop until the patient's residual vision is lost. The most serious disadvantage of laser surgery is that it can damage some of the macular nerves that react with light and cause some vision loss. Occasionally, vision loss due to surgery is as severe or more severe than when it is untreated. However, in some patients, the initial vision loss after laser surgery can prevent vision deterioration over time. Verteporfin has recently been used to treat wet MD. Cour, M., et al. 89179 200418455, Drugs Aging 19: 101-133 (2002). Fitphen is a vascular blocking photoreactive dye that is administered via injection. The dye moves towards the blood vessels that cause vision loss and is activated by a non-cauterizing flash that enters the eye in the presence of oxygen. Fitphen is mainly delivered into the blood plasma via lipoproteins. Activated fitterfin produces a highly reactive, short-lived single oxygen and reactive oxygen free radical, causing local damage to the neovascular endothelium. As a result, blood vessels are occluded. It is known that injured endothelium will release procoagulant and vasoactive factors through lipid-oxidase (leukotrienes) and cyclooxygenase (arachidoids such as prostamin) pathways, causing platelets to coagulate and form fibrin clot Blocks and vasoconstriction. Fitphen seems to tend to accumulate in new blood vessels, including choroidal new blood vessels. However, animal models show that Fitterfin also accumulates in the retina. Therefore, administration of Fitphen may damage retinal structures, including the retinal pigment epithelium and the outer nuclear layer of the retina. Another method currently used to treat MD is a drug-based antiangiogenic therapy. Cour, M., et al. Drugs Aging 19: 101-133 (2002). However, the first clinical trial using an anti-angiogenic agent: interferon-α failed to effectively treat MD, with high side effects. Arch. Ophthalmol. 115: 865-72 (1997). Intravitreal injection of triamcinolone is reported to suppress CNVM stigmatized by lasers in monkeys, but cannot prevent MD patients from severely losing their vision within one year in randomized trials. Gillies, M.C., et al., Invest. Ophthalmol Vis. Sci. 42: S522 (2001). Many other anti-angiogenic drugs have reached different stages of development for patients with MD, including vasostatic steroids (eg, anecortave acetate, Alcon drug) and vascular epithelial growth factor (VEGF) antibodies or Its fragment. Guyer, D.R., et al., Invest. 89179 200418455
Ophthalmol. Vis· Sci. 42:S522 (2001)。其中一種VEGF抗體為 rhuFab。其他用於治療MD之新藥物包括EYE101 (Eyetech藥 廠)、LY333531 (Eli Lilly藥廠)、米瓦特(Miravant)與利賽特 (RETISERT)植入劑(Bausch & Lomb藥廠),其可使類固醇滲入 眼中達三年之久。 雖然用於治療MD與相關黃斑變性之新穎且有效療法已 在探討中,但仍沒有有效之治療法。因此,相關技藝上需 要一種有效治療MD之方法。 選擇性細胞激素抑制性藥劑 一種稱為SelCIDsTM (Celgene公司)或選擇性細胞激素抑制 性藥劑已經合成及試驗。此等化合物可強力抑制TNF-α產 生,對LPS誘發ILlp與IL12具有適度抑制效果。L.G. Corral, 等人,Ann· Rheum· Dis. 58:(Suppl I) 1107-1113 (1999)。 選擇性細胞激素抑制性藥劑之其他特徵為其係強效之 PDE4抑制劑。PDE4為出現在人體脊髓及類淋巴系細胞中主 要磷酸二酯酶同功異構酶中之一種。該酵素在調節細胞活 性上扮演重要功能,其使普遍存在之第二信使者cAMP降 解,保持低度細胞内濃度。參見上述文獻。抑制PDE4活性 會造成cAMP濃度提高,即可調節LPS所謗發之細胞激素, 包括抑制單核細胞及淋巴細胞中TNF-α之產生。 【發明内容】 本發明包括治療與預防黃斑變性之方法,其包括對有此 需要之患者投予醫療或預防有效量之選擇性細胞激素抑制 性藥劑或其醫藥上可接受之鹽類、溶劑化物、水合物、立 89179 200418455 17::=形包合物或前藥。本發明亦包括處理 藥上可# A、, < k擇性細胞激素抑制性藥劑或其醫 ;==、溶劑化物、水合物、立體異構物、蘢 藥藥實施例包括以選擇性細胞激素抑制性 昱構物 之鹽類、溶劑化物、水合物、立體Ophthalmol. Vis. Sci. 42: S522 (2001). One of the VEGF antibodies is rhuFab. Other new drugs used to treat MD include EYE101 (Eyetech), LY333531 (Eli Lilly), Miravant and RETISERT implants (Bausch & Lomb) Allows steroids to penetrate the eyes for three years. Although new and effective therapies for MD and related macular degeneration are being explored, there are no effective treatments. Therefore, there is a need in the art for an effective treatment for MD. Selective cytokine inhibitory agents A drug called SelCIDsTM (Celgene) or selective cytokine inhibitory agents has been synthesized and tested. These compounds strongly inhibit the production of TNF-α, and have a moderate inhibitory effect on LPS-induced ILlp and IL12. L.G. Corral, et al. Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999). Selective cytokine inhibitory agents are also characterized by their potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes found in human spinal cord and lymphoid cells. This enzyme plays an important role in regulating cell activity, it degrades cAMP, a ubiquitous second messenger, and maintains a low intracellular concentration. See above. Inhibition of PDE4 activity will result in an increase in cAMP concentration, which can regulate the cytokines emitted by LPS, including inhibition of TNF-α production in monocytes and lymphocytes. [Summary of the Invention] The present invention includes a method for treating and preventing macular degeneration, which comprises administering to a patient in need thereof a medically or prophylactically effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt or solvate thereof. , Hydrate, Li 89179 200418455 17 :: = shaped inclusion compound or prodrug. The present invention also includes a selective cytokine-inhibitory agent or a medicament for treating drugs; ==, solvate, hydrate, stereoisomer, and peony. Examples include selective cells. Salts, solvates, hydrates, stereo
二形包合物或前藥,與其他適用於治療或預防MD 入/ ;且5使用,如(但不限於):類固醇、光敏化劑、整 ::、抗氧化劑、干擾素、黃嗓呤素衍生物、生長激素、Dimorphic inclusion compounds or prodrugs, and others suitable for the treatment or prevention of MD injections; and 5 use, such as (but not limited to): steroids, photosensitizers, whole ::, antioxidants, interferons, yellow throat Derivatives, growth hormones,
疒-性:血球因子、新血管形成作用之調節劑、抗-VEGF 血管擴增化合物,或其組合。激素“化合物或抗 本^另-項具體實施例包括治療、預防或處理應之方 遥包括對有此需要之患者投予醫療或預防有效量之選 =田胞激素抑制性藥劑或其醫藥上可接受之鹽類、溶劑 、水合物、立體異構物、蘢形包合物或前藥,與傳統 上用於治療或預防MD之療法組合,如(但不㈣):手術干 預(例如:雷射光致凝結療法與光動力療法)。 本發明尚包括適用於治療、預防與/或處理之醫藥組合 單位劑型及套組,其包含選擇性細胞激素抑制性 ^劑或其醫藥上可接受之鹽類、溶劑化物、水合物、立體 兴構物、蘢形包合物或前藥。 【實施方式】 89179 -10 - 200418455 本發明第一項具體實施例包括治療與預防MD之方法,其 包括對有此需要之患者(例如:哺乳動物如:人類)投予醫 療或預防有效量之選擇性細胞激素抑制性藥劑或其醫藥上 可接受之鹽類、溶劑化物、水合物、立體異構物、籠形包 合物或前藥。本發明尚有關治療或預防特異型MD及相關症 狀之方法,包括(但不限於)··萎縮型(乾型)MD、滲漏型(濕 型)MD、與老化有關之黃斑變性(ARM)、脈絡膜新血管形 成(CNVM)、視網膜色素上皮剝離(PED)及視網膜色素上皮萎 縮(RPE)。 本文所採用術語“黃斑變性”(MD)包括不論患者年齡之所 有黃斑變性疾病,但有些黃斑變性疾病較常見於某些年齡 層。其包括(但不限於):貝斯特疾病(Best’s disease)或卵黃型 (最常見於約7歲以下患者);斯塔加特症(Stargardt’s disease)、幼年型黃斑營養障礙或基底黃斑(最常見於約5至 約20歲患者);貝爾氏症(Behfs disease)、索斯比症(Sorsb/s disease)、道尼氏症(Doyne’s disease)或蜂巢狀營養障礙(最常 見於約30至約50歲患者);與老化有關之黃斑變性(最常見於 約60歲或以上患者)。 MD之原因包括(但不限於):遺傳、物理性創傷、疾病(如: 糖尿病)與感染,如:細菌感染(例如:痳瘋,特定言之ENL)。 本發明另一項具體實施例包括處理MD之方法,其包括對 需要此等處理之患者投予預防有效量之選擇性細胞激素抑 制性藥劑或其醫藥上可接受之鹽類、溶劑化物、水合物、 立體異構物、籠形包合物或前藥。 89179 -11 - 200418455 本發明另一項具體實施例包括一種醫藥組合物,其包含 選擇性細胞激素抑制性藥劑或其醫藥上可接受之鹽類、溶 劑化物、水合物、立體異構物、籠形包合物或前藥及視需 要選用之載劑。 本發明亦包括單一單位劑型,其包含選擇性細胞激素抑 制性藥劑或其醫藥上可接受之鹽類、溶劑化物、水合物、 立體兴構物、籠形包合物或前藥及可視需要選用之載劑。 本發明另一項具體實施例包括一種套組,其包括包含選 擇性細胞激素抑制性藥劑或其醫藥上可接受之鹽類、溶劑 化物、水合物、立體異構物、蘢形包合物或前藥之醫藥组 合物。本發明尚包括包含單一單位劑型之套組。本發明所 包括之套組可再包含其他活性劑。特定套組包含適用於檢 測或診斷MD之安斯樂網格(Amsler gHd)。 在不受理論限制下,咸信某些選擇性細胞激素抑制性藥 劑與其他可用於治療MD症狀之醫藥可依互補或促效之方 式治療或處理MD。因Λ,本發明一項具體實施例包括产 療、預防與/或處理MD之方法,其包括對有此等需要之电= 投予醫療或預防有效量之選擇性細胞激素㈣:藥劑^ 醫藥上可接受之鹽類、溶劑化物、水合物、立體異構物:、 籠形包合物或前藥,與醫療或預防有效 一 第二活性劑實例包括(但不限於)傳統用於^2劑。 之藥劑,如:類目醇、光敏化劑、整合辛、、=或預防助 擾素、黃嗓呤素衍生物、生長激素、趨中二化制、干 Τ丨王曰球^因早 新血管形成作用之調節劑、抗_VEGF抗體、前列腺素彳生 89179 -12. 200418455 素植物雌激素、消炎化合物或抗血管擴增化合物及其他 可見元例如· Physician’s Desk Reference 2003 中之藥劑。第二 活性叙特定f例包括(但不限於)菲㈣、普利停 、血管抑制性類固醇、伽㈣、干擾素如整合素、 抗氧化背!j與己g同可可驗。 、 入本發明亦包括醫藥組合物、單一單位劑型及套組,其包 含選擇性細胞激素抑制性藥劑或其醫藥上可接受之鹽類、 ::’!ί化物、水合物、立體異構物、籠形包合物或前藥與第 f活性劑。例如··套組可包含本發明化合物與類固醇、光 敏化劑、整合素、抗氧化劑、干擾素、黃嘌呤素衍生物、 生長激素、趨中性白血球因子、新血管形成作用之調節劑、 抗-VEGF抗體、前列腺素、抗生素、植物雌激素、消炎化合 物或抗血管擴增化合物,或其組合’或其他可解除或減: MD症狀之藥物。 咸信,特定選擇性細胞激素抑制性藥劑可減低或消除與 投予治療MD之藥劑有關之副作用,以提高對患者之投藥量 及/或提高患者之適應性。因此,本發明其他具體實施例包 括一種逆轉、減輕或避免MD患者與接受第二活性劑之投藥 有關之副作用,其包括對有此等需要之患者投予醫療 防有效量之選擇性細胞激素抑制性藥劑或其醫藥上可接: <鹽類、溶劑化物、水合物、立體異構物、籠形包合物 前藥。 3疒 -nature: Hematopoietic factors, modulators of neovascularization, anti-VEGF vaso-expansive compounds, or combinations thereof. Hormone "compounds or anti-antibiotics" Another specific embodiment includes treatment, prevention, or treatment should include the administration of a medically or prophylactically effective amount to a patient in need thereof Acceptable salts, solvents, hydrates, stereoisomers, osmium inclusion compounds or prodrugs in combination with therapies traditionally used to treat or prevent MD, such as (but not limited to): surgical intervention (eg: Laser photocoagulation therapy and photodynamic therapy). The present invention also includes a pharmaceutical combination unit dosage form and set suitable for treatment, prevention and / or treatment, which comprises a selective cytokine inhibitory agent or a pharmaceutically acceptable agent thereof. Salts, solvates, hydrates, stereostructures, osmium inclusion compounds or prodrugs. [Embodiments] 89179 -10-200418455 The first embodiment of the present invention includes a method for treating and preventing MD, which includes Administer a medically or prophylactically effective amount of a selective cytokine-inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate thereof to a patient in need thereof (eg, mammals such as humans) Substances, stereoisomers, clathrates or prodrugs. The present invention also relates to methods for treating or preventing specific MD and related symptoms, including (but not limited to) · atrophic (dry) MD, leakage Type (wet) MD, age-related macular degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED), and retinal pigment epithelial atrophy (RPE). The term "macular degeneration" ( MD) includes all macular degenerative diseases regardless of the patient's age, but some macular degenerative diseases are more common in certain age groups. They include (but are not limited to): Best's disease or yolk type (most commonly around 7 years old) The following patients); Stargardt's disease, juvenile macular dystrophy, or basal macula (most commonly in patients aged 5 to 20 years); Behfs disease, Sorsb / s disease), Doyne's disease, or honeycomb dystrophy (most common in patients about 30 to 50 years of age); macular degeneration associated with aging (most common in patients about 60 or older) The causes of MD include (but are not limited to): genetic, physical trauma, diseases (such as: diabetes) and infections, such as: bacterial infections (such as: leprosy, specifically ENL). Another specific embodiment of the present invention includes A method of treating MD, which comprises administering to a patient in need of such treatment a preventively effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt thereof, solvate, hydrate, stereoisomer, cage Inclusion compound or prodrug. 89179 -11-200418455 Another embodiment of the present invention includes a pharmaceutical composition comprising a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate thereof. , Stereoisomers, clathrates or prodrugs and optional carriers. The present invention also includes a single unit dosage form, which comprises a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereostructure, clathrate or prodrug thereof, and can be selected as required The carrier. Another embodiment of the present invention includes a kit comprising a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, osmium inclusion compound or Prodrug pharmaceutical composition. The invention also includes kits comprising a single unit dosage form. The set included in the present invention may further contain other active agents. Specific kits include Amsler gHd suitable for the detection or diagnosis of MD. Without being limited by theory, it is believed that some selective cytokine inhibitory agents and other medicines that can be used to treat the symptoms of MD can treat or treat MD in a complementary or pro-active manner. Because of Λ, a specific embodiment of the present invention includes a method for obstetrics, prevention, and / or treatment of MD, which includes electricity for such needs = administration of a medical or preventive effective amount of a selective cytokine ㈣: medicament ^ medicine Acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs, and are medically or preventively effective. Examples of second active agents include (but are not limited to) traditionally used ^ 2 Agent. Pharmacy, such as: class alcohols, photosensitizers, integrin, = or prevention of interferon, lutein derivatives, growth hormone, chemotherapeutic system, dry 丨 Wang Yueqiu ^ because of the new Regulators of angiogenesis, anti-VEGF antibodies, prostaglandin 89891-12. 200418455 phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, and other visible elements such as the agents in Physician's Desk Reference 2003. Specific examples of the second active species include (but are not limited to) phenanthrene, priton, vasostatic steroids, gamma, interferon such as integrin, and antioxidative enzymes. Both j and g can be tested. The invention also includes pharmaceutical compositions, single unit dosage forms and kits, which include selective cytokine inhibitory agents or their pharmaceutically acceptable salts, :: '! Hydrates, hydrates, stereoisomers , Clathrate or prodrug with f-th active agent. For example, the kit may include a compound of the present invention and a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrophil, a regulator of neoangiogenesis, an anti-angiogenic effect, -VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, or combinations thereof 'or other drugs that can relieve or reduce: MD symptoms. It is believed that certain selective cytokine inhibitory agents can reduce or eliminate the side effects associated with the administration of agents for the treatment of MD, in order to increase the dose to the patient and / or improve the patient's adaptability. Therefore, other specific embodiments of the present invention include a method for reversing, reducing or avoiding side effects associated with receiving a second active agent in patients with MD, including administering a medically effective amount of selective cytokine suppression to patients in need Sex drugs or their medicinal access: < Salts, solvates, hydrates, stereoisomers, clathrate prodrugs. 3
如本文中其他部份所討論,MD症狀可採用手術干預法仏 療,如(但不限於):光或雷射療法、放射療法、視網膜Z 89179 -13- 200418455 素上皮移植及網膜中心移位。在不受理論限制下,咸作, 由此等傳統療法與選擇性細胞激素抑制性藥劑組合使^之 有效性極高。因此,本發明包括_種治療、預防與/或處理 《方法’其包括在手術干預或其他傳統非藥物性療法之 月卜期間或之後投予選擇性細胞激素抑制性藥劑或其醫藥 上可接受之鹽類、溶劑化物、水合物、立體異構物:、蘢: 包合物或前藥。 / 激素抑制性華豳匕 田本發明使用之化合物包括消旋性、純立體異構性與高立體 井構性選擇性細胞激素抑制性藥劑,具有選擇性細胞激 抑制劑活性之立體異構性及純對映異構性化合物及其醫藥 上可接受之鹽類、溶劑化物、水合物、立體異構物、蘢: 包合物與前藥。本發明使用之較佳化合物係來自紐澤西^ Celgene么司之已知選擇性細胞激素抑制性藥劑肠TM)。 本又所知用且除非另有說明,否則術語“選擇性細胞激素 抑制性藥劑,,與“SelCIDs™,,包括小分子藥劑,例如:不為 肽、蛋白質、核酸、寡醣或其他大分子之小型有機分子。 較佳化合物可抑制TNF_a產生。該化合物亦對Lps所誘發之 βν、IL12具有適度抑制效果。更佳者,該化合物為pDE4 之強力抑制劑。 選擇性細胞激素抑制性藥劑之明確實例包括(但不限 方、)環狀亞胺類,其揭示於美國專利案號5,605,914與 5,463,063 ; 4 目專利案號 5,728,844、5,728,845、5,968,945、 6,180,644與6,518,281之環烷基醯胺類與環烷基腈類;美國專 89179 -14- 200418455 利案號5,801,195、5,736,570、6,046,221與 6,284,780之芳基醯胺 類(例如:一項具體實施例為N_苯甲醯基冬胺基_3-(3’,4,_二 甲氧冬基)-丙酿胺),亞胺/酿胺_類與醇類(例如:3 -g太酸亞 胺基-3-(3’,4’-二甲氧苯基)丙」,),其揭示於美國專利案號 5,703,098 ;琥珀醯亞胺類與馬來醯亞胺類(例如·· 3-(3ι,4,,5,6,_ 四氫献酸亞胺基)-3-(3’’,4,’-二甲氧苯基)丙酸甲酯),其揭示 於美國專利案號5,658,940;經亞胺基與醯胺基取代之烷醯基 異羥肟酸,其揭示於美國專利案號6,214,857與WO 99/06041 ;經取代之苯乙基砜,其揭示於美國專利案號6,011050與 6,〇20,358;經取代之亞胺類(例如:2_酞醯亞胺基_3_(3,,4,-二 甲氧苯基)丙燒),其揭示於美國專利案號6,429,221 ;經取代 之1,3,4·噚二唑類(例如:2-[1-(3•環戊基氧-4-甲氧苯基)_2_ (1,3,‘嘮二唑-2-基)乙基]-5-甲基異吲哚-i,3-二酮),其揭示於 美國專利案號6,326,388;經取代之苯乙烯之氰基與羧基衍生 物(例如:3,3-雙-(3,4-二甲氧苯基)丙酸腈),其揭示於美國 專利案號 5,929,117,6,130,226,6,262,101 與 6,479,554 ; 2-位置 經α-(3,4-二取代之苯基)烷基取代且4_與/或5-位置上經含氮 基團取代之異4哚啉-1-酮與異啕哚啉-1,3-二酮,其揭示於 WO 01/34606 ;與經亞胺基與醯胺基取代之醯基異羥肟酸類 (例如··(3-(1,3-二氧代異吲嗓淋-2-基)-3-(3-乙氧基-4-甲氧苯 基)丙醯胺基)丙酸酯,其揭示於WO 01/45702。本文所出示 之各專利案與專利申清案所杨7F内客已以引用之方式完全 併入本文中。 其他選擇性細胞激素抑制性藥劑屬於一種合成之化學化 89179 -15- 200418455 合物’其典型具體實施例包括3_(u_二氧代苯並切異+朵 2-基)-3-(3-環戊氧基-4-甲氧苯基)丙醯胺與3_(ι,3·二氧代_4_ 氮雜異⑼哚2-基)-3-(3,4-二甲氧苯基)_丙醯胺。 其他明確之選擇性細胞激素抑制性藥劑屬於一種非多肽 之環狀醯胺類,其揭示於美國專利案號5,698,579與 5,877,200 ’此二者之揭示内容已以引用之方式完全併入本文 中。代表性ί幕狀酸胺類包括如下式化合物: 0 H、 0 R\ /_(fH~(C^)-C-Rl2 R7 Η Η 其中η之數值為1、2或3 ; R5為鄰伸苯基、未取代或經1至4個分別獨立選自下列各 物組成之群中之取代基取代··硝基、氰基、三氟甲基、乙 酯基、甲酯基、丙酯基、乙醯基、胺甲醯基、乙醯氧基、 羧基、羥基、胺基、烷基胺基、二烷基胺基、醯基胺基、i 至1〇個碳原子之烷基、1至10個碳原子之烷氧基,與_基; R7為(i)苯基或經一個或多個分別獨立選自下列各物組成 之群中之取代基取代之苯基:硝基、氰基、三氟甲基、乙 酿基、甲酯基、丙酯基、乙醯基、胺甲醯基、乙酿氧基、 羧基、羥基、胺基、1至10個碳原子之烷基、1至1〇個碳原子 之燒氧基,與I®基;(ii)苯甲基,其係未取代或經1至3個選 自下列各物组成之群中之取代基取代:硝基、氯基、三氣 甲基、乙酯基、甲酯基、丙酯基、乙醯基、胺甲酿基、乙 醯氧基、羧基、羥基、胺基、1至10個碳原子之烷基、1至 89179 -16- 200418455 ίο個碳原子之烷氧基,與自基;(iii)莕基;與(iv)苯甲氧基; R12為-OH、1至12個碳原子之烷氧基,或As discussed elsewhere in this article, MD symptoms can be treated with surgical interventions such as (but not limited to): light or laser therapy, radiation therapy, retina Z 89179 -13- 200418455 prime epithelial transplantation and omental center displacement . Without being bound by theory, salty crops, such traditional therapies combined with selective cytokine inhibitory agents make them extremely effective. Accordingly, the present invention includes a method of treating, preventing, and / or treating a method that includes administering a selective cytokine inhibitory agent or a pharmaceutically acceptable method during or after surgical intervention or other traditional non-drug therapy. Salts, solvates, hydrates, stereoisomers :, hydrazone: clathrates or prodrugs. / Hormone-inhibiting Hua Hua Dian Tian The compounds used in the present invention include racemic, pure stereoisomerism, and high stereoselectivity cytokine inhibitory agents, and stereoisomerism with selective cytokinesis inhibitory activity. And pure enantiomeric compounds and their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, hydrazones: clathrates and prodrugs. A preferred compound for use in the present invention is a known selective cytokine inhibitory agent, Intestine TM, from Celgene®, New Jersey. The term "selective cytokine inhibitory agents," and "SelCIDs ™," as used herein and unless otherwise stated, includes small molecule agents, such as peptides, proteins, nucleic acids, oligosaccharides, or other large molecules Small organic molecules. Preferred compounds inhibit TNF_a production. The compound also has a moderate inhibitory effect on βν and IL12 induced by Lps. Even better, the compound is a potent inhibitor of pDE4. Specific examples of selective cytokine inhibitory agents include, but are not limited to, cyclic imines, which are disclosed in U.S. Patent Nos. 5,605,914 and 5,463,063; 4 Patent Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and Cycloalkylamines and cycloalkyl nitriles of 6,518,281; US patents 89179 -14- 200418455, arylamines of 5,801,195, 5,736,570, 6,046,221, and 6,284,780 (eg, a specific embodiment is N _Benzamyl winteramido_3- (3 ', 4, _dimethydonyl) -propanamine), imines / fermented amines_ and alcohols (for example: 3 -g tamate imide Phenyl-3- (3 ', 4'-dimethoxyphenyl) propyl ",), which is disclosed in U.S. Patent No. 5,703,098; succinimide and maleimide (for example, 3- ( 3,4,5,6, _tetrahydroacetic acid imino) -3- (3 '', 4, '-dimethoxyphenyl) propionic acid methyl ester), disclosed in U.S. Patent No. 5,658,940 ; Alkylimido hydroxamic acids substituted with imino and amidino groups, which are disclosed in US Patent Nos. 6,214,857 and WO 99/06041; substituted phenethyl sulfones, which are disclosed in US patents Case Nos. 6,011050 and 6, 〇20,358; Substituted imines (eg, 2-phthaloimino-3_ (3 ,, 4, -dimethoxyphenyl) propane), which are disclosed in the United States Patent No. 6,429,221; Substituted 1,3,4 · oxadiazoles (for example: 2- [1- (3 • cyclopentyloxy-4-methoxyphenyl) _2_ (1,3, 'fluorene Azole-2-yl) ethyl] -5-methylisoindole-i, 3-diketone), which is disclosed in US Patent No. 6,326,388; cyano and carboxy derivatives of substituted styrene (eg: 3,3-bis- (3,4-dimethoxyphenyl) propionitrile), which is disclosed in U.S. Patent Nos. 5,929,117,6,130,226, 6,262,101, and 6,479,554; 2-position via α- ( 3,4-Disubstituted phenyl) alkyl-substituted iso-4inolin-1-ones and isoxolinolin-1,3-diones substituted at the 4- and / or 5-position with nitrogen-containing groups , Which is disclosed in WO 01/34606; and fluorenyl hydroxamic acids substituted with imino and fluorenyl groups (eg, (3- (1,3-dioxoisoindolin-2-yl)) -3- (3-ethoxy-4-methoxyphenyl) propanamido) propionate, which is disclosed in WO 01/45702. Each of the patent cases and patent filings presented here, Yang 7F The subject has been incorporated herein by reference in its entirety. Other selective cytokine inhibitory agents are a synthetic chemical compound 89179 -15- 200418455. Typical examples include 3_ (u_dioxobenzochrysene Iso + Duo-2-yl) -3- (3-cyclopentyloxy-4-methoxyphenyl) propanamide and 3_ (ι, 3 · dioxo_4_azaisoisodinole 2-yl)- 3- (3,4-Dimethoxyphenyl) -propanamide. Other specific selective cytokine inhibitory agents belong to a class of non-polypeptide cyclic amidines, the disclosures of which are disclosed in U.S. Patent Nos. 5,698,579 and 5,877,200, both of which are fully incorporated herein by reference. Representative amines include compounds of the following formula: 0 H, 0 R \ / _ (fH ~ (C ^)-C-Rl2 R7 Η Η where η is 1, 2, or 3; R5 is adjacent extension Phenyl, unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of nitro, cyano, trifluoromethyl, ethyl, methyl, and propyl , Ethanoyl, carbamate, ethanoyloxy, carboxyl, hydroxy, amine, alkylamino, dialkylamino, fluorenylamino, alkyl with i to 10 carbon atoms, 1 Alkoxy groups of up to 10 carbon atoms, and _ groups; R7 is (i) phenyl or phenyl substituted by one or more substituents independently selected from the group consisting of: nitro, cyano Methyl, trifluoromethyl, ethyl, methyl, propyl, ethyl, carbamoyl, ethyloxy, carboxyl, hydroxy, amino, alkyl of 1 to 10 carbon atoms, Carbooxy group of 1 to 10 carbon atoms, and I group; (ii) benzyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: nitro , Chloro, trimethyl, ethyl, methyl, propyl , Acetamyl, carbamoyl, acetamyloxy, carboxyl, hydroxy, amine, alkyl of 1 to 10 carbon atoms, 1 to 89179 -16- 200418455 alkoxy of 1 carbon atom, and (Iii) fluorenyl; and (iv) benzyloxy; R12 is -OH, an alkoxy group of 1 to 12 carbon atoms, or
V R8為氲或1至1〇個碳原子之烷基;及 10 其中V R8 is fluorene or an alkyl group of 1 to 10 carbon atoms; and 10 wherein
R9為氫、1至1〇個碳原子之烷基…c〇r1G或·s〇2R R10為氫、1至ίο個碳原子之烷基或苯基。 此類之明確化合物包括(但不限於)·· 3-苯基-2-( 1_氧代異吲哚啉_2•基)丙酸; 3苯基-2-( 1-氧代異吲哚啉_2_基)丙醯胺·, 3-苯基_3-(1-氧代異吲哚啉基)丙酸; 3_苯基_3仆氧代異⑼哚琳_2_基)丙醯胺; 3-(4_甲氧苯基)-3仆氧代異⑼嗓琳-基)丙酸·, 3 (4甲乳丰基)_3仆氧代異射琳基)丙醯胺; (’甲氧苯基卜3^1·氧代異吲哚琳基)丙酸; 甲氧基—苯基氧代-1,3-二氫異吲哚-2-基)丙 醯胺; 7 3-(3,4-一 甲氧苯基)-3-Γ 1 t ,,, J (K虱代異吲哚啉-2-基)丙醯胺; 3-(3,4-二乙氧基苯基 ,^ ^ 氧代異吲哚啉-基)丙酸; 3-(1-氧代異吲哚啉·2 # 一 . 土-乙氧基-4-甲氧苯基)丙酸甲 酉0 , - (3-乙氧基-4-甲氧苯基)丙酸 _(3 -丙氧基-4-甲氧苯基)丙酸 -(3-丁氧基-4-甲氧苯基)丙酸 3-(1-氧代異吲哚啉基)_3 3-(1-氧代異吲哚啉基)_3 3-(1-氧代異吲哚啉_2_基)_3 89179 -17- 200418455 3-(1-氧代異⑻哚啉-2-基>3-(3-丙氧基-4-甲氧苯基)丙醯 胺; 3-(1-氧代異峋哚啉-2-基)-3-(3-丁氧基-4-甲氧苯基)丙醯 胺; 3_(1_氧代異啕哚啉-2-基)-3-(3-丁氧基-4-甲氧苯基)丙酸甲 酉旨;與 3-(1-氧代異4丨嗓# -2-基)-3-(3-丙氧基-4-甲氧苯基)丙酸甲 酉旨。 其他明確之選擇性細胞激素抑制性藥劑包括亞胺基與醯 胺基取代之烷醯基異羥肪酸,其揭示於WO 99/06041,其揭 示内容已以引用之方式完全併入本文中。此等化合物包括 (但不限於): 〇 rsA 严3 I ,n-ch; s R〆^ R5 (CnH^)—C—N-0-R4 R4· 其中各R1與R2分別獨立時,為氫、低碳數烷基,或R1與 R2可與其分別鍵結之碳原子共同形成鄰伸苯基、鄰伸莕基 或環己烯-1,2-二基、未取代或經1至4個分別獨立選自下列各 物組成之群中之取代基取代:硝基、氰基、三氟甲基、乙 @曰基、甲酿基、丙酿基、乙酿基、胺甲驗基、乙酿氧基、 羧基、羥基、胺基、烷基胺基、二烷基胺基、醯基胺基、1 至10個碳原子之烷基、1至10個碳原子之烷氧基與齒基; R3為經1至4個分別獨立選自下列各物組成之群中之取代 基取代之苯基··硝基、氰基、三氟甲基、乙酯基、甲酯基、 89179 -18- 200418455 丙酯基、乙醯基、胺甲醯基、乙醯氧基、複基、經基、胺 基、1至10個碳原子之烷基、1至10個碳原子之烷氧基、1至 10個碳原子之烷硫基、苯甲氧基、3至6個碳原子之環烷氧 基、C4_C6_環亞烷基甲基、C3_Cl()_亞烷基甲基、茚滿基氧與 鹵基; R4為氫、1至6個碳原子之烷基、苯基或苯甲基; R為氫或1至6個碳原子之统基; R5為-CH2-、_CH2_CO_、-S02-、-S-或 _NHCO_ ; η之數值為〇、1或2 ;及 該等含有可質子化之氮原子之化合物之酸加成鹽類。 其他用於本發明之明確選擇性細胞激素抑制性藥劑包括 (但不限於): 3-(3-乙氧基-4-甲氧苯基)_ν_羥基-3-( 1-氧代異吲哚啉基)丙 醯胺; 3-(3-乙氧基甲氧苯基)甲氧基-3-(1-氧代異吲哚啉基) 丙醯胺; N-苯甲氧基-3·(3·乙氧基冬甲氧苯基)-3•酞醯亞胺基丙醯 胺; Ν-苯甲氧基-3_(3·乙氧基冬甲氧苯基)_3_(3_硝基酞醯亞胺 基)丙醯胺; Ν-苯甲氧基Κ3-乙氧基_4_甲氧苯基氧代異吲哚啉 基)丙醯胺; 3-(3-乙氧基-4-甲氧苯基)_Ν_羥基-3-酞醯亞胺基丙醯胺; Nf基_3-(3,4-二甲氧苯基)冬g太醯亞胺基丙醯胺; 89179 -19- 200418455 3-(3-乙氧基-4-甲氧苯基)-Ν-輕基-3-(3-硝基酞醯亞胺基)丙 醯胺; N-經基-3-(3,4-二甲氧苯基氧代異吲噪琳基)丙醯 胺; 3-(3-乙氧基-4-甲氧苯基)-Ν-羥基-3-(‘甲基-酞醯亞胺基) 丙醯胺; 3-(3-環戊氧基-4-甲氧苯基)-Ν-羥基-3-酞醯亞胺基丙醯胺; 3-(3-乙氧基-4-甲氧苯基)_Ν_羥基-3气1,3_二氧代_2,3_二氫 -1Η_苯並[f]異蚓哚-2-基)丙醯胺; N-羥基-3-{3-(2-丙氧基M-甲氧苯基卜3-酞醯亞胺基丙醯 胺; 3-(3-乙氧基-4-甲氧苯基)-3-(3,6_二氟欧醯亞胺基)·ν_羥基 丙酸胺; 3-(4-胺基酞醯亞胺基)-3-(3-乙氧基-4_甲氧苯基)_Ν_羥基丙 醯胺; 3_(3_胺基酞醯亞胺基)-3-(3-乙氧基-4-甲氧苯基)_ν_經基丙 醯胺; Ν-幾基-3-(3,4-二甲氧苯基)_3_(1_氧代異十呆淋基)丙酿 胺; 3-(3-環戊氧基_4·甲氧苯基)_Ν韻_3仆氧代異令卜 丙醯胺;與 N-苯甲氧基1(3-乙氧基_4_甲氧笨基彳 基)丙醯胺。 4M3-硝基酜驢亞胺 其他用於本發明之選擇性細胞數 ^ 京抑制性藥劑包括苯基 89179 -20- 200418455 上經氧代異啕哚基取代之經取代之苯乙基砜。此等化合物 實例包括(但不限於)彼等揭示於美國專利案號6,〇2〇,358中 R5R9 is hydrogen, an alkyl group of 1 to 10 carbon atoms ... c0r1G, or · s〇2R R10 is hydrogen, an alkyl group or phenyl group of 1 to 10 carbon atoms. Such clear compounds include, but are not limited to, 3-phenyl-2- (1-oxoisoindolin-2-yl) propionic acid; 3phenyl-2- (1-oxoisoindole Indolin_2_yl) propanamidin, 3-phenyl_3- (1-oxoisoindololinyl) propionic acid; 3-phenyl_3 ) Propanamide; 3- (4_methoxyphenyl) -3 oxo-isoisopropane-yl) propionic acid, 3 (4-methyl lactyl) _3 oxoisometyl) propionate Amine; ('methoxyphenylbu 3 ^ 1 · oxoisoindolinyl) propionic acid; methoxy-phenyloxo-1,3-dihydroisoindol-2-yl) propanamide ; 7 3- (3,4-monomethoxyphenyl) -3-Γ 1 t ,,, J (K-Isoindolin-2-yl) propanamide; 3- (3,4-di Ethoxyphenyl, ^^ oxoisoindolin-yl) propionic acid; 3- (1-oxoisoindolinline · 2 # a. Earth-ethoxy-4-methoxyphenyl) propene Acid formamidine 0,-(3-ethoxy-4-methoxyphenyl) propionic acid_ (3-propoxy-4-methoxyphenyl) propionic acid- (3-butoxy-4-methyl Oxophenyl) propanoic acid 3- (1-oxoisoindolinyl) _3 3- (1-oxoisoindolinyl) _3 3- (1-oxoisoindolinyl_2_yl) _3 89179 -17- 200418455 3- (1-oxygen Isoxolinolin-2-yl > 3- (3-propoxy-4-methoxyphenyl) propanamide; 3- (1-oxoisooxolin-2-yl) -3- ( 3-butoxy-4-methoxyphenyl) propanamide; 3 -_ (1-oxoisoxolinolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propane Formic acid methyl ester; with 3- (1-oxoiso4 丨 lar # -2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid methyl ester. Other clear choices Sexual cytokine inhibitory agents include imino and amidino-substituted alkanoyl isohydroxy fatty acids, which are disclosed in WO 99/06041, the disclosure of which is fully incorporated herein by reference. These compounds include (But not limited to): 〇rsA Yan 3 I, n-ch; s R〆 ^ R5 (CnH ^) — C—N-0-R4 R4 · Where each R1 and R2 are independent, they are hydrogen and low carbon number Alkyl, or R1 and R2 may form an o-phenylene, o-phenylene, or cyclohexene-1,2-diyl group, unsubstituted or independently selected from 1 to 4 respectively Substituent substitution in the group consisting of: nitro, cyano, trifluoromethyl, ethyl @ ayyl, methyl ethyl, propyl ethyl, ethyl ethyl, aminomethyl, ethyl ethyl, Carboxy Group, hydroxyl, amine, alkylamino, dialkylamino, fluorenylamino, alkyl of 1 to 10 carbon atoms, alkoxy and dentyl of 1 to 10 carbon atoms; R3 is 1 to 4 phenyl substituted by a substituent independently selected from the group consisting of the following: nitro, cyano, trifluoromethyl, ethyl, methyl, 89179 -18- 200418455 propyl Base, ethenyl, carbamoyl, ethenyloxy, compound, warp, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, 1 to 10 Alkylthio of carbon atom, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C4_C6_cycloalkylenemethyl, C3_Cl () _ alkylenemethyl, indanyloxy and halo ; R4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R is hydrogen or a radical of 1 to 6 carbon atoms; R5 is -CH2-, _CH2_CO_, -S02-, -S -Or _NHCO_; the value of η is 0, 1 or 2; and acid addition salts of compounds containing protonatable nitrogen atoms. Other specifically selective cytokine inhibitory agents useful in the present invention include, but are not limited to: 3- (3-ethoxy-4-methoxyphenyl) _ν_hydroxy-3- (1-oxoisoindole Indolinyl) propanamide; 3- (3-ethoxymethoxyphenyl) methoxy-3- (1-oxoisoindololinyl) propanamide; N-benzyloxy-3 · (3 · Ethoxy Winter Methoxyphenyl) -3 · phthaloiminoimidopropanamine; Ν-Benzyloxy-3_ (3 · Ethoxy Winter Methoxyphenyl) _3_ (3_ nitrate Phthalocyanine imino) propanamidin; N-benzyloxyK3-ethoxy_4-methoxyphenyloxoisoindolinyl) propanamidin; 3- (3-ethoxy- 4-methoxyphenyl) _N_hydroxy-3-phthalimidoimidopropanamine; Nf group_3- (3,4-dimethoxyphenyl) dong g taiimidoimidopropanamide; 89179 -19- 200418455 3- (3-ethoxy-4-methoxyphenyl) -N-lightyl-3- (3-nitrophthaloamidoimino) propanamide; N- meso-3- (3,4-Dimethoxyphenyloxoisoindolyl) propanamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-('methyl- Phthamidamido) Propanamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthaloamidopropylamidoamine; 3- (3- Ethoxy-4-methoxyphenyl) _N_hydroxy-3 gas 1,3_dioxo_2,3_dihydro-1fluorene_benzo [f] isoeartholin-2-yl) propanamide ; N-Hydroxy-3- {3- (2-propoxyM-methoxyphenyl) 3-phthalimidoimidopropanamine; 3- (3-ethoxy-4-methoxyphenyl) -3- (3,6_difluorocarbamidoimino) · ν_hydroxypropionic acid amine; 3- (4-aminophthaloamidoimino) -3- (3-ethoxy-4_methyl Oxyphenyl) _N_hydroxypropylamidine; 3_ (3-aminophthaloamidoimino) -3- (3-ethoxy-4-methoxyphenyl) _ν_meridylpropylamidine; Ν- Isopropyl-3- (3,4-dimethoxyphenyl) _3_ (1_oxoisodecylyl) propanamine; 3- (3-cyclopentyloxy_4 · methoxyphenyl) _Ν Rhyme_3 isoxoisostilbamine, and N-benzyloxy 1 (3-ethoxy_4_methoxybenzylidene) propanamide. 4M3-nitropyridine The number of selective cells of the present invention includes inhibitory phenyl ethyl sulfone substituted with oxoisofluorinyl on phenyl 89179-20-20200418455. Examples of such compounds include (but are not limited to) them R5 disclosed in U.S. Patent No. 6,02,358
Y為 〇〇、ch2、s〇2或 ch2C=〇 ;各 Rl、r2、以3與 r4分別獨 ,為氫、商基、丨至4個碳原子之烷基、丨至4個碳原子之烷 氧3基、4硝基、氰基、羥基或_NR8R9;或相鄰碳原子上Rl、R2、 R3與r45中任二者可與所示之伸苯基環共同形成亞颯基; 各R5與R6分別獨立為氫、個碳原子之垸基、個碳 原,之烷氧基、氰基或至多18個碳原予之環烷氧基; 者’其揭示内容已以引用之方式完全併入本文中,包括下 式化合物: 其中有*標記之碳原子構成對掌性中心; R為产基、⑴個碳原子之垸基、苯基、苯甲基或皿8’r9,; 各R與R9分別獨立為氫、!至8個碳原子之燒基、苯基或苯 甲基,或R8與R9中之一 A薪,x 7 8 9 為虱另—個為-COR10或-S02R10,或 &與化共同形成四亞甲基、 兄丁丞 五亞甲基、六亞甲基或 -CH2CH2X CH2CH2-,其中 χΐ為七… 9, 或-ΝΗ-;及 各R R分別獨立為氫、1至8個卢 田f >8, Q, 原子之烷基、苯基或苯 甲基,或R8與R9’中之一為辦, —、〇8, ^ 9, 、、、二 另一個為-COR10,或-S02R10, 或R與R共同形成四亞甲基、 οττ ^ττ 2 五亞甲基、六亞甲基或 -CH2CH2X CH2CH2_,其中:^為 _s•或-ΝΗ-。 89179 -21 - 200418455 咸了解,雖然為了方便而以苯乙基砜代表上述化合物, 但其包括當R7為NR8’R9’時之磺醯胺。 此等化合物之明確實例為彼等式中γ為c==〇或CH2者。 另一種此等化合物之明確化合物為彼等式中各Rl、R2、 R3與R4分別獨立為氫、鹵基、甲基、乙基、甲氧基、乙氧 基、硝基、氰基、羥基或-NR8R9者,其中各以與R9分別獨立 為氫或甲基或R8與R9中之一為氫,另一個為/〇CH3。 特別之化合物為彼等式中Rl、R2、“與以中之一為_NH2, 其餘R1、R2、R^R4為氫。 特別之化合物為彼等式中、R2、以與R4中之一為 -NHCOCH3,其餘 R1、R2、R3與 R4為氫。 特別之化合物為彼等式中Rl、R2、R3與&中之一為 -N(CH3)2,其餘 Rl、R2、以與 R4為氫。 、 此等化合物之另一種較佳化合物為彼等式中R1、R2、R3 與R4中I 一為甲基,其餘Rl、R2、r^r4為氫。 特別之化合物為彼等式中、R2、 餘R1、R2、R3與R4為氫。 、R3與R4中之一為氟,其 1為氮、甲基、 ^戊氧基或環己 特別之化合物為彼等式中“與R6分別獨 乙基、丙基'甲氧基、乙氧基、丙氧基、 氧基。 特別之化合物為彼等式中R5為甲氧基 基、多環烷氧基與苯並環烷氧基。Y is 〇〇, ch2, s02 or ch2C = 〇; each of R1, r2, 3 and r4 are respectively hydrogen, commercial group, alkyl group of 4 to 4 carbon atoms, and 4 to 4 carbon atoms Alkoxy 3yl, 4nitro, cyano, hydroxyl or _NR8R9; or any of R1, R2, R3 and r45 on adjacent carbon atoms may form a fluorenylene group with the phenylene ring shown; each R5 and R6 are independently hydrogen, fluorenyl group of one carbon atom, carbon atom, alkoxy group, cyano group or cycloalkoxy group of up to 18 carbon atoms; Incorporated herein, including compounds of the following formula: wherein the carbon atoms marked with * constitute the center of the palm; R is a sulfonyl group, a fluorenyl group of one carbon atom, a phenyl group, a benzyl group, or an 8'r9, each R and R9 are independently hydrogen ,! An alkyl group, phenyl or benzyl group of 8 carbon atoms, or one of R8 and R9, x 7 8 9 is lice and the other is -COR10 or -S02R10, or & Methylene, butyl pentamethylene, hexamethylene or -CH2CH2X CH2CH2-, where χΐ is seven ... 9, or -ΝΗ-; and each RR is independently hydrogen, 1 to 8 Lutian f > 8, Q, atomic alkyl, phenyl or benzyl, or one of R8 and R9 'is-, 〇8, ^ 9, ,,, and two are -COR10, or -S02R10, Or R and R together form tetramethylene, οττ ^ ττ 2 pentamethylene, hexamethylene, or -CH2CH2X CH2CH2_, where: ^ is _s • or -ΝΗ-. 89179 -21-200418455 It is understood that although the above compounds are represented by phenethylsulfone for convenience, it includes sulfonamide when R7 is NR8'R9 '. Clear examples of these compounds are those in which γ is c == 0 or CH2. Another clear compound of these compounds is that each of R1, R2, R3 and R4 in their formula is independently hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxyl Or -NR8R9, each of which is independently hydrogen or methyl, and one of R8 and R9 is hydrogen, and the other is / 0CH3. A special compound is one of R1, R2, "and one of them in the formula is _NH2, and the remaining R1, R2, R ^ R4 is hydrogen. A special compound is one of their formula, R2, and R4 Is -NHCOCH3, and the remaining R1, R2, R3, and R4 are hydrogen. A special compound is -N (CH3) 2 in one of R1, R2, R3, and & Is hydrogen. Another preferred compound of these compounds is that in R1, R2, R3, and R4, one of them is a methyl group, and the remaining R1, R2, r ^ r4 are hydrogen. A special compound is their formula R2, R2, R2, R3, and R4 are hydrogen. One of R3 and R4 is fluorine, and 1 is nitrogen, methyl, pentyloxy, or cyclohexyl. The specific compounds are "and R6 is monoethyl, propyl'methoxy, ethoxy, propoxy, and oxy, respectively. Specific compounds are those in which R5 is methoxy, polycycloalkoxy and benzocycloalkoxy.
甲氧基,R6為單環烷氧 ‘且R6為乙氧基。 甲基、乙基、苯基、 89179 -22- 200418455A methoxy group, R6 is a monocycloalkoxy group, and R6 is an ethoxy group. Methyl, ethyl, phenyl, 89179 -22- 200418455
特別之化合物為彼等式中R7為甲基、 苯 、乙基、苯基、苯甲 基或NR8’9’,其中各R8,與R9,分別獨立為氫或甲基。 特別之化合物為彼等式中R7為甲基。 特別之化合物為彼等式中R7為NR8,9,,其中各R8,與R9,分別 獨立為氫或甲基。 其他明確之選擇性細胞激素抑制性藥劑包括氟烷氧基取 代4 1,3-二氫-異吲哚基化合物,其揭示於美國臨時申請案 號60/436,975 (頒與G· Muller等人,2002年12月30日申請),其 揭示内容已以引用之方式完全併入本文中。代表性氟燒氧 基-取代之1,3-二氫-異吲嗓基化合物包括下式化合物: ,〇 一 R1Special compounds are those in which R7 is methyl, benzene, ethyl, phenyl, phenyl or NR8'9 ', wherein each of R8, and R9 is independently hydrogen or methyl. A particular compound is that in which R7 is methyl. A special compound is that in the formula, R7 is NR8,9, wherein each of R8, and R9 is independently hydrogen or methyl. Other well-defined selective cytokine inhibitory agents include fluoroalkoxy substituted 4 1,3-dihydro-isoindolyl compounds, which are disclosed in U.S. Provisional Application No. 60 / 436,975 (issued to G. Muller et al., Filed December 30, 2002), the disclosure of which is fully incorporated herein by reference. Representative fluoroalkyloxy-substituted 1,3-dihydro-isoindolinyl compounds include compounds of the formula:
其中: Y 為-C(O)-、-CH2、-ch2c(o)-、-c(o)ch2-或 so2; Z為-Η、-C(0)R3、-(Coq-fe 基)-S〇2-(Ci_4-燒基)、-Cn燒基、 -CH2OH、CHaOKCw烷基)或-CN;Where: Y is -C (O)-, -CH2, -ch2c (o)-, -c (o) ch2-, or so2; Z is -Η, -C (0) R3,-(Coq-fe group) -S〇2- (Ci_4-alkyl), -Cn alkyl, -CH2OH, CHaOKCw alkyl) or -CN;
Ri與R2分別獨立為-CHF2、-Ci·8·抗基、_C3.18環燒基或1(r 烷基)(C3-18-環烷基),1^與R2中至少一個為CHF2 ; R3為-NR4R5、-烷基、-OH、-O-烷基、苯基、苯甲基、經取 代之苯基或經取代之苯甲基; R4與R5分別獨立為-Η、-Cw烷基、-OH、-0C(0)R6 ; 89179 -23- 200418455 R6為-Cm-烷基、-胺基(Cy烷基)、·苯基、-苯甲基或_芳基; Xi、X2、X3與X4分別獨立為-H、-卣素、-硝基、-NH2、-CF3、 -Cw烷基、-(C〇_4-烷基)-(Cw環烷基)、(Cw烷基)-NR7R8 、(C〇_4-燒基)-N(H)C(0)-(R8)、(C0-4-燒基)-N(H)C(0)N(R7R8)、 (c〇_4_烷基)_n(h)c(o)o(r7r8)、(CG_4-烷基)_or8、(Cg 4_烷基)_ 咪唑基、(CG-4_烷基)-吡咯基、(Cw烷基)-呤二唑基或(C〇 燒基)-三也基,或Xi、X2、X3、與X4中二者可共同結合形成 環燒基或雜環燒基環(例如:X2、χ2與與、I 與X3、X2與X4或X^X4可形成3、4、5、6或7員環,其可為 芳香系,藉以與異啕p朵基環形成雙環系);及 R與R分別獨jl為Η、Cn烷基、c3-6·環烷基、(Cu-燒基)_ (c3-6_環燒基)、(cw燒基)-n(r7R8)、(Ci6•烷基)_〇r8、苯基、 苯甲基或芳基; 或其醫藥上可接受之鹽類、溶劑化物、水合物、立體異 構物、籠形包合物或前藥。 本發明較佳化合物包括(但不限於): 3-(4-乙醯基胺基-1,3-二氧代q,%二氫_異啕哚基)_3_(夂 環丙基甲氧基-4-二氟甲氧基-笨基 > 丙酸; 3-(4-乙醯基胺基-1,3-二氧代4,3·二氫_異⑼哚_2_基)_3·(3_ 裱丙基甲氧基-4_二氟甲氧基-笨基)_Ν,Ν_二甲基·丙醯胺; 3-(4-乙醯基胺基_1,3_二氧代4,3_二氫_異ρ引哚-2_基广3_(3環 丙基甲乳基-4-一氟甲氧基-苯基)_丙酸胺; 3-(3-環丙基甲氧基-4_二氟甲氧基_苯基)冬(1,3_二氧代 -1,3-二氫-異4卜朵-2-基)-丙酸; 89179 -24- 200418455 3-(3-¾丙基甲氧基-4-二氟甲氧基-苯基)-3-(l,3-二氧代 -1,3-二氯-異丨嗓-2-基)-N-經基-丙驢胺; 3-(3-環丙基甲氧基-4-二氟甲氧基苯基)-3-(7-硝基-1-氧代 -1,3-二氫-異吲哚-2-基)-丙酸甲酯; 3-(3-環丙基甲氧基-4-二氟甲氧基_苯基)-3-(7-硝基-1-氧代 -1,3·二氯-異4丨嗓-2-基)-丙酸; 3-(3-環丙基甲氧基-4-二氟甲氧基-苯基-3-(7-硝基-1-氧代 -1,3-二氫·異吲哚-2-基)-)-N,N-二甲基·丙醯胺; 3-(7-胺基-1-氧代-1,3-二氫-異蚓哚-2-基)-3-(3-環丙基甲氧 基-4-二氟甲氧基·苯基)-N,N-二甲基-丙醯胺; 3-(4-二氣甲乳基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二 氫-異啕哚-2-基)-丙酸甲酯; 3-(7-胺基-1-氧代-1,3-二氫-異啕哚-2-基)-3-(4-二氟甲氧基 -3-乙氧基-苯基)-丙酸甲酯; 3-[7-(環丙烷羰基-胺基)-1-氧代-1,3-二氫-異吲哚-2-基]-3-(4-二氣甲氧基-3 -乙氧基-苯基)-丙酸甲醋; 3-(7_乙酸基胺基-1-乳代-1,3-二氯-異β丨嗓-2-基)-3-(4-二氣 甲氧基-3-乙氧基-苯基)-丙酸甲酯; 3-(7-乙醒基胺基-1-氧代-1,3-二氯-異4丨嗓-2-基)-3-(4-二氣 甲氧基-3-乙氧基-苯基)-丙酸; 3 -[7-( ί幕丙坑談基-胺基)-1 -氧代-1,3-二氮-異丨嗓-2-基]-3-(4-二氟甲氧基-3 -乙氧基-苯基)-丙酸; 環丙烷羧酸{2-[2-胺甲醯基-1-(4-二氟甲氧基-3-乙氧基-苯 基)-乙基]-3-氧代-2,3-二氫-1H-異吲哚-4-基}-醯胺; 89179 -25- 200418455 環丙烷羧酸{2-[l-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基 胺甲醯基-乙基]-3-氧代-2,3-二氫-IH-異啕哚-4-基}-; 環丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羥基 胺甲醯基-乙基]-3-氧代-2,3-二氫-1H-異吲哚_4_基卜醯胺; 3-(7-乙醯基胺基-1-氧代-1,3-二氫-異啕哚-2-基)-3-(4-二氟 甲氧基-3-乙氧基-苯基)_丙醯胺; 3-(7-乙酸基胺基-1-氧代-1,3_二氫-異Θ丨嗓-2-基)-3-(4-二氟 甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙醯胺; 3-(7-乙醯基胺基-1-氧代-1,3-二氫-異啕哚-2-基)-3-(4-二氟 甲氧基-3-乙氧基-苯基)-N-羥基-丙醯胺; 3-(4-乙醯基胺基_1,3_二氧代-1,3-二氫-異4丨哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸; 3-(4-乙醯基胺基-1,3-二氧代-1,3-二氫-異啕哚-2-基)-3-(4-一氣甲氧基-3-乙氧基)-丙醒胺; 3_(4_乙醯基胺基-1,3-二氧代-1,3-二氫-異㈤哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基·丙醯胺; 3-(4-乙醯基胺基-1,3-二氧代-1,3-二氫-異啕哚-2-基)-3-(4-二鼠甲氧基-3-乙氧基-苯基)-N-經基-丙S盛胺; 環丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲磺 驢基]-3-乳代-2,3-二氮- l-異丨嗓-4-基}-睡胺; N-{ 2-[1-(4-二氣甲氧基-3-乙氧基-苯基)-2-甲績酸基-乙 基]-1,3-二氧代-2,3-二氫-1-異啕哚-4-基}-乙醯胺;與 環丙烷羧酸{2-[2-胺甲醯基-1-(4-二氟甲氧基-3-乙氧基·苯 基)-乙基]-7-鼠-3-氧1代-2,3-二氮-1-異4丨口朵-4-基}-醒胺。 89179 -26- 200418455 其他選擇性細胞激素抑制性藥劑包括7_醯胺基-取代之異 啕哚基化合物,其示於美國臨時申請案號6〇/454,155 (頒與 G· Muller等人,2003年3月12日申請),其揭示内容已以引用 之方式完全併入本文中。代表性7_醯胺基取代之異4丨哚基 化合物包括如下式化合物:Ri and R2 are independently -CHF2, -Ci · 8 · antiyl, _C3.18 cycloalkyl or 1 (r alkyl) (C3-18-cycloalkyl), and at least one of 1 ^ and R2 is CHF2; R3 is -NR4R5, -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; R4 and R5 are independently -fluorene and -Cw alkane , -OH, -0C (0) R6; 89179 -23- 200418455 R6 is -Cm-alkyl, -amino (Cyalkyl), · phenyl, -benzyl or aryl; Xi, X2 , X3 and X4 are independently -H, -fluorene, -nitro, -NH2, -CF3, -Cw alkyl,-(C0_4-alkyl)-(Cw cycloalkyl), (Cw alkane Group) -NR7R8, (C0_4-alkyl) -N (H) C (0)-(R8), (C0-4-alkyl) -N (H) C (0) N (R7R8), (c〇_4_alkyl) _n (h) c (o) o (r7r8), (CG_4-alkyl) _or8, (Cg 4-alkyl) _imidazolyl, (CG-4_alkyl)- Pyrrolyl, (Cw alkyl) -pyridazolidyl or (Co alkyl) -triyl, or Xi, X2, X3, and X4 can be combined to form a cycloalkyl or heterocycloalkyl ring (For example: X2, χ2 and and, I and X3, X2 and X4, or X ^ X4 can form a 3, 4, 5, 6, or 7-membered ring, which can be aromatic, whereby and啕 p aryl ring forms a bicyclic ring system); and R and R are independently Η, Cn alkyl, c3-6 · cycloalkyl, (Cu-alkyl) _ (c3-6_cycloalkyl), ( cw alkyl) -n (r7R8), (Ci6 • alkyl) _〇r8, phenyl, benzyl or aryl; or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers thereof , Clathrate or prodrug. Preferred compounds of the present invention include (but are not limited to): 3- (4-ethylamidoamino-1,3-dioxoq,% dihydro_isofluorinyl) _3_ (fluorenecyclopropylmethoxy -4-difluoromethoxy-benzyl > propanoic acid; 3- (4-ethylamidoamino-1,3-dioxo 4,3 · dihydro_isopyridin_2_yl) _3 · (3_ propylmethoxy-4_difluoromethoxy-benzyl) _N, N_dimethyl · propanamide; 3- (4-ethylamidoamino_1,3_dioxy Generation 4,3_dihydro_isopyridine-2_ylcan 3_ (3-cyclopropylmethyllactyl-4-monofluoromethoxy-phenyl) _propionic acid amine; 3- (3-cyclopropyl Methoxy-4_difluoromethoxy_phenyl) winter (1,3_dioxo-1,3-dihydro-iso4-butor-2-yl) -propionic acid; 89179 -24- 200418455 3- (3-¾propylmethoxy-4-difluoromethoxy-phenyl) -3- (l, 3-dioxo-1,3-dichloro-iso-2-acyl-2-yl ) -N-Cyclopropylpropanamine; 3- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -3- (7-nitro-1-oxo-1,3 -Dihydro-isoindol-2-yl) -propionic acid methyl ester; 3- (3-cyclopropylmethoxy-4-difluoromethoxy_phenyl) -3- (7-nitro- 1-oxo-1,3 · dichloro-iso4 (l-2--2-yl) -propionic acid; 3- (3-cyclopropylmethoxy-4-di Methoxy-phenyl-3- (7-nitro-1-oxo-1,3-dihydro · isoindole-2-yl)-)-N, N-dimethyl · propanamide; 3- (7-amino-1-oxo-1,3-dihydro-isoearmidin-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy · benzene ) -N, N-dimethyl-propanamide; 3- (4-diaminomethyllactyl-3-ethoxy-phenyl) -3- (7-nitro-1-oxo-1 , 3-Dihydro-isoxazol-2-yl) -propionic acid methyl ester; 3- (7-amino-1-oxo-1,3-dihydro-isoxazol-2-yl) -3 -(4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester; 3- [7- (cyclopropanecarbonyl-amino) -1-oxo-1,3-dihydro -Isoindole-2-yl] -3- (4-dimethoxymethoxy-3 -ethoxy-phenyl) -methyl propionate; 3- (7_acetamido-1-lactone -1,3-dichloro-isoβ 丨 -2-yl) -3- (4-dimethoxymethoxy-3-ethoxy-phenyl) -propionic acid methyl ester; 3- (7-ethyl Alkylamino-1-oxo-1,3-dichloro-iso4 丨 hex-2-yl) -3- (4-diaminomethoxy-3-ethoxy-phenyl) -propionic acid ; 3-[7- (ί Screen propyl alkynyl-amino) -1 -oxo-1,3-diazine-iso-2-methyl] -3- (4-difluoromethoxy- 3-ethoxy-phenyl) -propionic acid; cyclopropanecarboxylic acid {2- [2-amine formamidine -1- (4-difluoromethoxy-3-ethoxy-phenyl) -ethyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl}-醯Amine; 89179 -25- 200418455 Cyclopropanecarboxylic acid {2- [l- (4-difluoromethoxy-3-ethoxy-phenyl) -2-dimethylamine formamyl-ethyl]- 3-oxo-2,3-dihydro-IH-isopyridin-4-yl}-; cyclopropanecarboxylic acid {2- [1- (4-difluoromethoxy-3-ethoxy-benzene ) -2-hydroxyaminomethylamidino-ethyl] -3-oxo-2,3-dihydro-1H-isoindole-4-ylpyridamine; 3- (7-ethylamidoamine -1-oxo-1,3-dihydro-isoxazol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propanamide; 3- ( 7-Acetylamino-1-oxo-1,3_dihydro-isoΘ 丨 hex-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl)- N, N-dimethyl-propanamide; 3- (7-ethylamidoamino-1-oxo-1,3-dihydro-isoamido-2-yl) -3- (4-di Fluoromethoxy-3-ethoxy-phenyl) -N-hydroxy-propylammonium; 3- (4-ethylamidoamino_1,3-dioxo-1,3-dihydro-iso 4 丨 Indol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid; 3- (4-ethylfluorenylamino-1,3-dioxo -1,3-dihydro-isoxanthenyl-2-yl) -3- (4-one gas methoxy -3-ethoxy) -propanamine; 3- (4-ethylamidoamino-1,3-dioxo-1,3-dihydro-isoamido-2-yl) -3- (4 -Difluoromethoxy-3-ethoxy-phenyl) -N, N-dimethyl · propanamide; 3- (4-ethylamidoamino-1,3-dioxo-1, 3-dihydro-isopyridin-2-yl) -3- (4-dimurylmethoxy-3-ethoxy-phenyl) -N-acryl-propylamine; cyclopropanecarboxylic acid { 2- [1- (4-Difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl] -3-lacto-2,3-diaza-l-iso 丨 丨- 4-yl} -pyrimidine; N- {2- [1- (4-diaminomethoxy-3-ethoxy-phenyl) -2-formyl-ethyl] -1,3- Dioxo-2,3-dihydro-1-isoamidine-4-yl} -acetamidine; and cyclopropanecarboxylic acid {2- [2-aminomethylamido-1- (4-difluoromethyl) Oxy-3-ethoxy · phenyl) -ethyl] -7-murine-3-oxo-2,3-diazine-1-iso-4-oxo-4-yl} -pentamine. 89179 -26- 200418455 Other selective cytokine inhibitory agents include 7-amido-substituted isordinyl compounds, shown in U.S. Provisional Application No. 60 / 454,155 (issued to G. Muller et al. , Filed on March 12, 2003), the disclosure of which has been fully incorporated herein by reference. Representative 7-fluorenyl-substituted iso-4-ole compounds include compounds of the following formula:
其中: Y為(:(0)-、-CH2、-CH2C(0)-或 S〇2 ; X為Η ; ζ為(C〇_4-燒基)-C(0)R3、Cm-垸基、(C〇.4-燒基)-〇H、(Ci-4-烷基)-0((^-4-烷基)、(Cw烷基 hSOKCM·烷基)、(C0-4-烷基)-SCKCw烷基)、(cG_4-烷基)-NH2、(CG_4-烷基)-NKCu-烷基)2、 (C〇_4_烷基)-N(H)(OH)、CH^SOKCm·烷基); 心與R2分別獨立為烷基、環烷基或-(Cm-烷基)環烷 基, R3為-NR4R5、—〇H或-CKCu-烷基); R4 為 Η ; R5為 _ΟΗ或 _0C(0)R6 ; R為-Cn燒基、-胺基(Ci_8-燒基)、(Ci-8-燒基)-(C3_6-稼坑基) 、C3-6-環烷基、苯基、苯甲基或芳基; 或其醫藥上可接受之鹽類、溶劑化物、水合物、立體異 89179 -27- 200418455 構物、籠形包合物或前藥;或如下式化合物 〇Where: Y is (: (0)-, -CH2, -CH2C (0)-or S〇2; X is Η; ζ is (C〇_4-alkyl) -C (0) R3, Cm- 垸Group, (C0.4-alkyl) -OH, (Ci-4-alkyl) -0 ((^-4-alkyl), (Cw alkylhSOKCM · alkyl), (C0-4- Alkyl) -SCKCw alkyl), (cG_4-alkyl) -NH2, (CG_4-alkyl) -NKCu-alkyl) 2, (C0_4-alkyl) -N (H) (OH), CH ^ SOKCm · alkyl); and R2 are independently alkyl, cycloalkyl, or-(Cm-alkyl) cycloalkyl, R3 is -NR4R5, -OH or -CKCu-alkyl); R4 is Η; R5 is _ΟΗ or _0C (0) R6; R is -Cn alkyl group, -amine group (Ci_8-alkyl group), (Ci-8-alkyl group)-(C3_6-carbyl group), C3- 6-cycloalkyl, phenyl, benzyl or aryl; or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers 89179 -27- 200418455 structures, clathrates or prodrugs ; Or a compound of the following formula.
其中: a Y為 _C(0)-、-CH2、-ch2c(o)_或 s〇2; X為卣素、-CN、-NR7R8、-N〇2或-CF3 ; W為Where: a Y is _C (0)-, -CH2, -ch2c (o) _, or s〇2; X is halogen, -CN, -NR7R8, -N〇2, or -CF3; W is
2為(C0-4烷基)402((^-4-烷基)、-(C〇-4烷基)-CN、-(Co-4烷基)_ C(〇)R3、Cm-烷基、(CG_4-烷基)OH、(CG.4-烷基)0((^.4-烷基)、 (C〇十烷基 POCCm-烷基)、(CG-4-烷基)NH2、(CG.4-烷基)Νβυ-境基)2、(CG_4-烷基)Ν(Η)(ΟΗ)或(C〇-4-烷基)NSOKCm-烷基); WS-C3_6-環烷基、-(Cu-烷基)-(C3-6環烷基)、_(C〇-8-烷基)-⑴3-6環烷基)-NR7R8、(C〇-8-烷基)-nr7r8、(CG_4-烷基)-CHR9-坑基)-NR?R8, 反1與R2分別獨立為Cw烷基、環烷基或(Cw-烷基)環燒基; 89179 -28- 200418455 以3為 Cw烷基、NR4R5、〇_(c w烷基); R與R5分別獨立為H、Ci 8-烷基、(C(^烷基HCw環烷 基)、〇H或-〇c(〇)r6 ; R為Cl·8-^基、(CW烷基:KC3_6_環烷基)、胺基-(Ci-8-烷 基)'苯基、苯甲基或芳基; R7與R8分別獨立為H、Cy烷基、(C㈣烷基hc3_6-環烷基)、 苯基、苯甲基、芳基,或可與所附接之原子共同形成3至7 員雜環烷基或雜芳基環; 燒基、(C(M_烷基)芳基、(cw烷基hC3 6•環烷 基)、(Cq-4·燒基)-雜環;或 其醫藥上可接受之鹽類、溶劑化物、水合物、立體異構 物、籠形包合物或前藥。 其他選擇性細胞激素抑制性藥劑包括N•烷基_異羥肟酸_ 異⑼嗓基化合物’其示於美國臨時申請案號6〇/454,149 (頒 與G· Muller等人,2003年3月12日申請),其揭示内容已以引 用之方式完全併入本文中。代表性N_烷基_異羥肋酸_異吲哚 基化合物包括如下式化合物:2 is (C0-4alkyl) 402 ((^-4-alkyl),-(C〇-4alkyl) -CN,-(Co-4alkyl) _C (〇) R3, Cm-alkane (CG_4-alkyl) OH, (CG.4-alkyl) 0 ((^. 4-alkyl), (C〇decylPOCCm-alkyl), (CG-4-alkyl) NH2 ((CG.4-alkyl) Nβυ-alkyl), (CG_4-alkyl) N (Η) (ΟΗ) or (C〇-4-alkyl) NSOKCm-alkyl); WS-C3_6-ring Alkyl,-(Cu-alkyl)-(C3-6cycloalkyl), _ (C〇-8-alkyl) -⑴3-6cycloalkyl) -NR7R8, (C〇-8-alkyl) -nr7r8, (CG_4-alkyl) -CHR9-pit group) -NR? R8, trans 1 and R2 are independently Cw alkyl, cycloalkyl or (Cw-alkyl) cycloalkyl; 89179 -28- 200418455 Let 3 be Cw alkyl, NR4R5, 〇 (cw alkyl); R and R5 are independently H, Ci 8-alkyl, (C (^ alkylHCw cycloalkyl), OH or -〇c ( 〇) r6; R is Cl · 8- ^ group, (CW alkyl group: KC3_6-cycloalkyl group), amino- (Ci-8-alkyl) 'phenyl group, benzyl group or aryl group; R7 and R8 They are independently H, Cy alkyl, (C alkyl alkyl hc3_6-cycloalkyl), phenyl, benzyl, aryl, or they can form a 3 to 7-membered heterocycloalkane with the attached atom Or heteroaryl ring; alkyl, (C (M_alkyl) aryl, (cw alkyl hC3 6 • cycloalkyl), (Cq-4 · alkyl) -heterocyclic; or pharmaceutically acceptable Accepted salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. Other selective cytokine inhibitors include N • alkyl_hydroxamate_isoamidine compounds' It is shown in US Provisional Application No. 60 / 454,149 (issued to G. Muller et al., Filed on March 12, 2003), the disclosure of which is fully incorporated herein by reference. Representative N_ Alkyl-isohydroxyribanoic acid-isoindolyl compounds include compounds of the formula:
其中: Y為-C(O)-、-CH2、-ch2C(〇)4 s〇2 ; 1^與 R2分別獨 JL 為 CU8-烷基、CF2H、CF3、CH2CHF2、環烷 89179 -29- 200418455 基或(Cm-烷基)環烷基,· ZA Η、Cw烷基、_NH2-NR3R4或 OR5 ; Z2為 Η或 C(0)R5 ;Where: Y is -C (O)-, -CH2, -ch2C (〇) 4 s〇2; 1 ^ and R2 are respectively JL is CU8-alkyl, CF2H, CF3, CH2CHF2, naphthenic 89179 -29- 200418455 Or (Cm-alkyl) cycloalkyl, · ZA Η, Cw alkyl, _NH2-NR3R4 or OR5; Z2 is Η or C (0) R5;
Xi、X2、X3與 X4分別獨立為 Η、鹵素、N02、OR3、CF3、-c卜6_ 烷基、-(C0_4-烷基)-(C3_6-環烷基)、(C〇_4_烷基)_N(R8R9)、(C〇-4-烷基)-NHC(〇HR8)、(c0.4-烷基)-NHC(0)N(R8)(R9)、(C0.4-烷 基)-NHC(0)N(R8R9)、(C〇-4-烷基)-NHC(0)0(R8)、(CG_4-烷基) -o-r8、(cG_4-烷基)-咪唑基、(cG.4-烷基)·吡咯基、(CG.4-烷基)_ 口亏二峻基、(C〇_4_奴基)-三嗤基或(Cw燒基)-雜環; R3、R4與R5分別獨立為Η、Cw烷基、O-Cu烷基、苯基、 苯甲基或芳基; R6與R7分別獨立為Ci.6-烷基; R·8與R9分別獨立為Η、Cyfe基、C3·6·環總基、(Cn燒 基)_(c3_6-環烷基)、(CG-6-烷基)-N(R4R5)、(Cu-烷基)-〇R5、苯 基、苯甲基、芳基、六氫P比淀基、六氫7比p井基、峨洛淀基、 嗎啉基或c3_7-雜環烷基;或 其醫藥上可接受之鹽類、溶劑化物、水合物、立體異構 物、籠形包合物或前藥。 明確之選擇性細胞激素抑制性藥劑包括(但不限於): 2-[1七3·乙氧基-4-甲氧苯基)-2-甲基-磺醯基乙基]異蚓嗓 琳-1-酮; 2-[1-(3·乙氧基-4-甲氧苯基)-2-(N,N-二甲基-胺基磺醯基) 乙基]異4丨嗓琳-1-酮; 2-[ 1-(3-乙氧基-4-甲氧苯基)-2-甲基-磺醯基乙基]異4嗓 89179 -30- 200418455 口林-1,3-二酉同; 2-[ 1-(3-乙氧基-4-甲氧苯基)-2-甲基-磺醯基乙基]-5-硝基-異4丨嗓淋-1,3 -一酉同, 2-[1-(3-乙氧基-4-甲氧苯基)-2-甲基-磺醯基乙基]-4-硝基 異4丨嗓淋-1,3-^ —酬, 2-[ 1-(3-乙氧基-4-甲氧苯基)-2-甲基磺醯基乙基]-4-胺基異 吲哚啉二酮; 2_fM3-乙氧基-4-甲氧苯基)-2-甲基磺醯基乙基]-5-甲基異 W嗓淋-1,3-二酮, 2-[ 1-(3-乙氧基-4-f氧苯基甲基績醯基乙基]乙醯胺 基異i丨嗓p林-1,3-二_, 2-[1-(3-乙氧基-4-f氧苯基)-2_甲磺醯基乙基卜‘二甲基胺 基異4丨嗓4 -1,3-二_, 2^-(3-乙氧基-4_f氧笨基)_2_甲基橫酿基乙基]-5·二甲基 胺基異4丨嗓P林_1,3_二奶 2_[H3-乙氧基-4- f氧苯基)_2_甲基磺醯基乙基]苯並Μ 異β卜朵琳- 二酮; 2_[Κ3-乙氧基-4- f象笨基)_2_甲基績酿基乙基]_4-甲氧基 異4丨嗓淋- 二酮; \(3_環戊氧基-4-f氧苯基)_2·甲基續酿基乙基-胺; 2_[ H3-環戊氧基-^氧苯基)-2·甲基磺醯基乙基]異啕 哚啉_1,3-二酮;與 4* - f氧冬基)""2-甲基石買酿基乙基]-4- -甲 2-[1-(3_環戊虱基-4 」一甲 〆固同0 基胺基異卩?丨哚啉-1,3一〆 -31 - 89179 200418455 其他選擇性細胞激素抑制性藥劑包括揭示於美國專利案 10/392,195 (2003年3月19曰申請);國際專利申請案號 PCT/US03/0873 (2003年3月20日申請);美國臨時專利申請案 號6〇M38,45〇與60/438,448 (頒與G· jailer等人,此二者均於 2003年1月7曰申請);與美國臨時專利申請案號6〇/452,46〇 (頒與G· Muller等人,於2003年3月5日申請)中之純對映異構 性化合物,該等文獻之揭示内容已以引用之方式完全併入 本文中。較佳化合物包括2-[1-(3_乙氧基甲氧苯基)甲基 磺醯基乙基]-4-乙酸基胺基異吲哚啉4,3-:酮之對映異構 物與3_(3,4·二甲氧基-苯基)_3_(i•氧代],3_二氫_異吲哚 基)-丙醯胺之對映異構物。 本發明所使用之較佳選擇性細胞激素抑制性藥气為 3_(3,4_二甲氧基-苯基)_3_(1氧代_u_二氫-異十来I基^丙 醯胺與環丙烷羧酸{2-[H3_乙氧基_4_甲氧基_苯基)_2_甲磺 醯基-乙基]-3-氧代-2,3-二氫._異吲哚冰基卜酿胺,其可得 自 Celgene公司(Warren,NJ)。3_(3,4二甲氧基 _苯基氧代 -1,3-二氫-異4哚-2-基)·丙醯胺之化學結構式如下: 0〆Xi, X2, X3 and X4 are independently fluorene, halogen, N02, OR3, CF3, -c and 6-alkyl,-(C0_4-alkyl)-(C3_6-cycloalkyl), and (C〇_4_alkane) Group) _N (R8R9), (C〇-4-alkyl) -NHC (〇HR8), (c0.4-alkyl) -NHC (0) N (R8) (R9), (C0.4-alkane Group) -NHC (0) N (R8R9), (C〇-4-alkyl) -NHC (0) 0 (R8), (CG_4-alkyl) -o-r8, (cG_4-alkyl) -imidazole Group, (cG.4-alkyl) · pyrrolyl, (CG.4-alkyl) _biose, (C0_4_yl) -trimethyl or (Cw-alkyl) -hetero Ring; R3, R4 and R5 are each independently fluorene, Cw alkyl, O-Cu alkyl, phenyl, benzyl or aryl; R6 and R7 are independently Ci.6-alkyl; R · 8 and R9 They are independently fluorene, Cyfe group, C3 · 6 · ring total group, (Cn alkyl) _ (c3_6-cycloalkyl), (CG-6-alkyl) -N (R4R5), (Cu-alkyl) -〇R5, phenyl, benzyl, aryl, hexahydro P-pyridyl, hexahydro 7-p-pyridyl, erodolide, morpholinyl, or c3_7-heterocycloalkyl; or pharmaceutically acceptable Accepted salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. Specific selective cytokine inhibitory agents include (but are not limited to): 2- [1 Hepta-3 · ethoxy-4-methoxyphenyl) -2-methyl-sulfomethylethyl] isoammonium -1-one; 2- [1- (3 · ethoxy-4-methoxyphenyl) -2- (N, N-dimethyl-aminosulfonyl) ethyl] iso-4- -1-one; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] iso-4891891-30-30 200418455 Koulin-1,3 -Dioxin is the same; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -5-nitro-iso4 丨 laryn-1, 3 -Identical, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -4-nitroiso4 丨 laryn-1, 3-^-Pay, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolinline dione; 2_fM3- Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -5-methylisopropane-1,3-dione, 2- [1- (3-ethoxy -4-f-oxyphenylmethylphenethylethyl] acetamidoisoline 1-line-1,3-di-, 2- [1- (3-ethoxy-4-foxybenzene ) -2_methanesulfonylethylethyl'dimethylaminoiso4 丨 4 -1,3-di_, 2 ^-(3-ethoxy-4_f oxygen Group) _2_methyltransmethylethyl] -5 · dimethylaminoiso4 丨 Prin_1,3_ 二奶 2_ [H3-ethoxy-4-foxyphenyl) _2_methyl Sulfofluorenylethyl] benzoM iso-β-bordolin-dione; 2_ [Κ3-ethoxy-4-f like benzyl) _2_methylphenethylethyl] _4-methoxyiso 4 丨 Vinyl-dione; \ (3_cyclopentyloxy-4-foxyphenyl) _2 · methylcontinuous ethyl-amine; 2_ [H3-cyclopentyloxy- ^ oxyphenyl) -2 · Methylsulfonylethyl] isoxolinoline 1,3-dione; and 4 * -f-oxoyl) " " 2-Methylsulfonylethyl] -4- -Methyl 2- [1- (3_cyclopentyl-4 "monomethyl isothiophene? Isoline-1,3 monopyridine-31-89179 200418455 Other selective cytokine inhibitory Medicaments include those disclosed in US Patent No. 10 / 392,195 (filed on March 19, 2003); International Patent Application No. PCT / US03 / 0873 (filed on March 20, 2003); US Provisional Patent Application No. 6〇 M38,45〇 and 60 / 438,448 (issued to G. Jailer et al., Both of which were filed on January 7, 2003); and US Provisional Patent Application No. 60 / 452,46〇 (issued to G. Muller et al., Applied on March 5, 2003 ) Of the enantiomerically pure compound, the disclosure of these documents have been completely incorporated by reference herein. Preferred compounds include the enantiomers of 2- [1- (3-ethoxymethoxyphenyl) methylsulfonylethyl] -4-acetamidoisoindolinoline 4,3-: one Enantiomers of the compound and 3_ (3,4 · dimethoxy-phenyl) _3_ (i • oxo), 3_dihydro_isoindolyl) -propanamide. The preferred selective cytokine-inhibiting medicinal gas used in the present invention is 3_ (3,4_dimethoxy-phenyl) _3_ (1oxo_u_dihydro-isoselecyl) propylamidine With cyclopropanecarboxylic acid {2- [H3_ethoxy_4_methoxy_phenyl) _2_methanesulfonyl-ethyl] -3-oxo-2,3-dihydro._isoindole Indomethacrylamine, available from Celgene (Warren, NJ). The chemical structure of 3_ (3,4dimethoxy_phenyloxo-1,3-dihydro-iso4indol-2-yl) · propanamide is as follows: 0〆
環丙燒羧酸{2-[1·(3-乙氧基_4_甲氧基_苯基)_甲續酿基_乙 基]-3-氧代_2,3_二氫_1Η·異㈣_4•基卜醯胺,其化學結構式 如下: 89179 -32- 200418455Cyclopropanecarboxylic acid {2- [1 · (3-ethoxy_4_methoxy_phenyl) _methylene_ethyl] -3-oxo_2,3_dihydro_1Η · Isoamidine_4 • Gibmidine, its chemical structural formula is as follows: 89179 -32- 200418455
个赏明化合物 利公土案所揭$日3^衣本又所揭示專利案或專 才“ 口木所揭說明〈万法製備。此 予 行不對稱合成法合成或使用已 μ學性組成可進 其他標準合成有機化學技術製備。⑴士手性Η王及 本文所採用且除非另有說明, 鹽類,,包括該術語所提及化人物^二吾醫樂上可接受之 麵。可接…主祕n供毒性酸與鹼加成鹽 已知之有機與無機酸或鹼 1技* 酸、磷酸、硫酸、甲〜 括例如:鹽酸、氫溴 ▲甲% 、乙酸 '酒石酸 檸檬酸、蘋果酸、馬來酸、 "〜:、 7km ^ 木鉍、烏頭酸(aconitic acid)、 夂%、酞鉍、雙羥萘酸、庚酸,等等 呈酸性質之化合物可與多種醫藥上可接受之驗形成鹽 頒。可用於製備此等酸性化合 鹽類之驗為彼等可形…二f上可接受之驗加成 ^ ”、、母丨生鹼加成鹽類者,亦即含有醫 美上可接受之陽離子之躏 " 土金屬鹽類,特定於)驗金屬或驗 驗類包括(但不限於;:Ν:二:或:… 膽鹼、二乙醇胺、? …基乙二胺、氯普魯卡因、 r A * 乙一胺、甲基葡糖胺(N-甲基葡糖胺)、離 胺酸與普魯卡因。 ; 否則術語“前藥”指可於生 、氧化或進行其他反應以 本文所採用且除非另有說明, 物條件(活體内或活體外)下水解 89179 200418455 產生母化合物之該化合物之衍生物。前藥實例包括(但不限 於)·包含可生物水解之部份基團,如··可生物水解之醯胺 類、可生物水解之酯類、可生物水解之胺甲酸酯類、可生 物水解之碳酸酯類、可生物水解之脲類及可生物水解之磷 酸酯類似物之選擇性細胞激素抑制性藥劑之衍生物。其他 岫藥貫例包括包含_N0、_N〇2、_〇N〇4 _〇N〇2部份基團之選 擇性細胞激素抑制性藥劑之衍生物。該等前藥主要採用習 知之方法製備,如彼等說明於i Burger,s Medicinal Chemis” a:d Drug DiScovery,172-178, 9体982 (Μαη_ Ε·彻打編輯, 第5版’ 1995年),與Design 〇f Pr〇drugs (H驗咖㈣編輯,In the case of a compound named Ligongtu, it was disclosed in a patent case or a specialist in "Koumoto", "Moufa". This method can be synthesized by asymmetric synthesis, or it can be made using μ Prepared by other standard synthetic organic chemistry techniques. Master Chi Chi Wang and the salt used in this article unless otherwise stated, including salts mentioned in the term ^ Ego medically acceptable face. Can be accessed … Secretary n For organic and inorganic acids or bases known for toxic acid and base addition salts * Acids, phosphoric acids, sulfuric acid, formaldehyde ~ Including, for example: hydrochloric acid, hydrobromide ▲%, acetic acid 'tartaric acid citric acid, malic acid , Maleic acid, " ~ :, 7km ^ wood bismuth, aconic acid, 夂%, bismuth phthalate, pamoic acid, heptanoic acid, etc. Compounds with acidic properties can be used with a variety of medically acceptable The test results in the formation of salt. The tests that can be used to prepare these acidic compound salts are tangible ... the acceptable test additions on the second f ^, the parent alkaloid addition salts, which also contains medical Beautifully acceptable cations " earth metal salts, specific) gold test OR tests include (but are not limited to :: N: Di: or: ... choline, diethanolamine,? ... ylethylenediamine, chloroprocaine, rA * ethylene monoamine, methylglucamine (N -Methyl glucosamine), lysine and procaine .; otherwise the term "prodrug" refers to a biological condition (in vivo or Hydrolysis in vitro) 89179 200418455 to produce derivatives of the compound of the parent compound. Examples of prodrugs include (but are not limited to) · containing some groups that are biohydrolyzable, such as ... Hydrolyzed esters, biohydrolyzable urethanes, biohydrolyzable carbonates, biohydrolyzable ureas and derivatives of selective cytokine inhibitors of biohydrolyzable phosphate analogs. Others Examples of peony drugs include derivatives of selective cytokine inhibitory agents containing _N0, _N〇2, _〇N〇4 _〇NO2. These prodrugs are mainly prepared by conventional methods, As stated in i Burger, s Medicinal Chemis ”a: d Dr ug DiScovery, 172-178, 9-body 982 (edited by Μαη_Ε · 彻 打, 5th edition ‘1995), and Design 〇f Pr〇drugs (edited by
Elselvier,New Y0rk 1985)中者。 , 、本^所採用且除非另有說明,否則術語“可生物水解之醯 胺頦 可生物水解之酯類”、“可生物水解之胺甲酸酯 類”、“可生物水解之碳酸醋類,,、“可生物水解之脲類”與“可 生物水解之磷酸酯類,,分別指化合物之醯胺、酯類、胺甲酸 酯類、碳酸酯類、脲類或磷酸酯類,該化合物:丨)不會干 擾化合物之生物活性,但賦與化合物有利之活體内性質, 々吸收性、作用持續期或作用開始時間;或2)無生物活 性::可於活體内轉化成生物活性化合物。可生物水解之 酉旨類貫例包括(但不限^):低碳數燒基g旨類、低碳數酸氧 ,烷基酿類(如:乙醯氧甲醋、乙醯氧乙酿、胺基羰基氧甲 酉:、特戊醯氧甲酯及特戊醯氧乙酯)、内酯基酯(如:酞基 與:代酞基酯)、低碳數烷氧醯氧烷基酯(如:甲氧羰基 氧-曰乙氧叙基氧乙酯與異丙氧羰基氧乙酯)、烷氧烷基 89179 -34 - 200418455 酯、膽鹼酯與醯胺基烷基酯(如:乙醯胺基甲酯)。可生物 水解之醯胺實例包括(但不限於):低碳數烷基醯胺、α-胺基 酸醯胺、烷氧醯基醯胺與烷基胺基烷基羰基醯胺。可生物 水解之胺甲酸酯之實例包括(但不限於)··低碳數烷基胺 類、經取代之乙二胺、胺基酸、羥烷基胺類、雜環與雜芳 香胺類與聚醚胺類。 多種選擇性細胞激素抑制性藥劑含有一個或多個對掌性 中心,可出現對映異構物之消旋混合物或非對映異構物之 混合物。本發明包括此等化合物之純立體異構型之用途及 彼等型式之混合物之用途。例如:包含等量或不等量選擇 性細胞激素抑制性藥劑之對映異構物之混合物可用於本發 明方法與組合物。本文所揭示明確化合物之純化之(R)或(S) 對映異構物實質上可不含其另一種對映異構物。 本文所採用且除非另有說明,否則術語“純立體異構性” 指組成中包含化合物之一種立體異構物且實質上不含該化 合物之另一種立體異構物。例如:具有一個對掌性中心之 化合物之純立體異構物組成實質上不含該化合物之相對對 映異構物。具有兩個對掌性中心之化合物之純立體異構物 組成實質上不含該化合物之其他非對映異構物。典型之純 立體異構性化合物包含約80重量%以上該化合物之其中一 種立體異構物及約20重量%以下該化合物之其他立體異構 物,更佳為約90重量%以上該化合物之其中一種立體異構物 及約10重量%以下該化合物之其他立體異構物,甚至更佳為 約95重量%以上該化合物之其中一種立體異構物及約5重量 89179 -35- 200418455 %以下該化合物之其他立體異構物。最佳為約97重量%以上 該化合物之其中一種立體異構物及約3重量%以下該化合 物之其他立體異構物。 本文所採用且除非另有說明,否則術語“高立體異構性” 指組成中包含約60重量%以上該化合物之其中一種立體異 構物,較佳為約70重量%以上,更佳為約80重量%以上該化 合物之其中一種立體異構物。 本文所採用且除非另有說明,否則術語“純對映異構性” 指具有一個對掌性中心之化合物之純立體異構性組成。同 樣地,“高對映異構性”指具有一個對掌性中心之化合物之 高立體異構性組成。 咸了解,若所示之結構式與所指定之名稱不符時,以所 出示之結構式為主。此外,若結構式之立體化學或結構式 之一部份未以例如:粗線或虛線表示時,該結構式或結構 式之一部份將包括其所有立體異構物。 第二活性劑 第二活性劑可與選擇性細胞激素抑制性藥劑共同用於本 發明方法與組合物中。較佳具體實施例中,第二活性劑可 抑制或解除黃斑受損病症,產生抗血管擴增作用或消炎效 應,或確使患者舒適。 第二活性劑實例包括(但不限於):類固醇、光敏化劑、 整合素、抗氧化劑、干擾素、黃嘌呤素衍生物、生長激素、 趨中性白血球因子、新血管形成作用之調節劑、抗-VEGF 抗體、前列腺素、抗生素、植物雌激素、消炎化合物、抗 89179 -36- 200418455 血管擴增化合物,其他已知可抑制或解除MD症狀之藥劑及 其醫藥上可接受之鹽類、溶劑化物、水合物、立體異構物、 籠形包合物、前藥與醫藥活性代謝物。某些具體實施例中, 該第二活性劑為菲特芬、普利停(purlytin)、血管抑制性類固 醇、rhuFab、干擾素_2α或己嗣可可驗(pentoxifylline) 〇 光敏化劑實例包括(但不限於)菲特芬、抑普琳錫(tin etiopurpurin)與莫特吩鑛(motexafin lutetium)。菲特芬可用於治 療濕型 MD。Cour,M·,等人,Drugs Aging 19:101-133 (2002)。 菲特芬為一種血管阻斷性光反應性染料,可經由注射投藥。 黃嘌呤素衍生物實例包括(但不限於):己酮可可鹼。 抗-VEGF抗體包括(但不限於):rhuFab。 類固醇實例包括(但不限於):9-貌-11,21-二羥基-16,17_1-甲基亞乙基雙(氧)孕-1,4-二烯-3,20-二酮。 前列腺素F2a衍生物實例包括(但不限於):萊坦普 (latanoprost)(參見美國專利案號6,225,348,其揭示内容已以 引用之方式完全併入本文中)。 抗生素實例包括(但不限於):四環素與其衍生物、利福 平(rifamycin)與其衍生物、大環内酯與甲硝達唑 (metronidazole)(參見美國專利案號 6,218,369與 6,015,803,其揭 示内容已以引用之方式完全併入本文中)。 植物雌激素實例包括(但不限於):染料木黃酮、染料木 苷、6’-0-Mal染料木苷、6’-0-Ac染料木苷、木質素異黃酮、 大豆苷(daidzin)、6’_0_Mal大豆苷、6’-0-Ac大豆嘗、黃豆黃 素、黃豆黃苷(glycitin)、6’-0-Mal黃豆黃苷、美皂異黃酮 89179 -37- 200418455 (biochanin) A、花黃素異黃酮(formononetin)與其混合物(參見 美國專利案號6,001,368,其揭示内容已以引用之方式完全併 入本文中)。 消炎劑實例包括(但不限於):去炎松(triamcinolone)乙驢胺 與地墓美松(dexamethasone)(參見美國專利案號5,770,589,其 揭示内容已以引用之方式完全併入本文中)。 抗血管擴增作用化合物包括(但不限於):沙利竇邁 (thalidomide)與選擇性細胞激素抑制性藥物(IMiDs™,Celgene Corp.,N.J.) 〇 干擾素實例包括(但不限於):干擾素-2α。 另一項具體實施例中,第二活性劑為穀胱甘肽(參見美國 專利案號5,632,984,其揭示内容已以引用之方式完全併入本 文中)。 生長激素實例包括(但不限於):鹼性纖維母細胞生長因 子(bFGF)與轉化生長因子b (TGF_b)。 趨中性白血球因子實例包括(但不限於)··腦衍生之趨中 性白血球因子(BDNF)。 新血管形成作用調節劑實例包括(但不限於):2型血纖維蛋 白溶酶原活化因子(PAI-2)。 其他可用於治療MD之藥物包括(但不限於)·· EYE101 (Eyetech藥廠)、LY333531 (Eli Lilly藥廒)、米瓦特(Miravant) 與利賽特(RETISERT)植入劑(Bausch & Lomb藥廒)。 治療輿預防之方法 本發明包含預防、治療與/或處理多種MD之方法。 -38- 89179 200418455 本文所採用且除非另有誇日M,π 3月口、則術語“預防MD,,、“治療 =與處理庸,包括(但不限於)抑制或降低與_有關之一 =夕種症狀之嚴重性。與MD有關之症狀及相關症候群包 括(但Γ限於):基底中白黃色㈣園之脈絡膜μ、黃斑 下之盤狀結症組織、脈故脸甚 脈…胰祈血官形成、視網膜色素上皮 」、視網艇色素上皮萎縮、自脈絡膜(緊臨視網膜下方之 富含血管組織層)長出血f、視力模糊或視野扭曲、中心盲 點、色素異常、在布#赫膜邮心職)内部連绪沉積 一層細粒物質與布魯赫膜增厚及通透性降低。 本又所知用JL除非另有說明,否則術語“治療婦,,指在開 始出、現MD症狀後投予本發明化合物或其他活性劑,其中 “預防”指在症狀開始前(特別指有MD危險之患者)投藥。有 罹患MD危險《患者實例包括(但不限於):6〇歲以上之老年 人與罹患如(但不限於)··糖尿病與痲瘋(例如·· enl)之患者。 有MD家族病史之患者亦為予員防療法之較佳候選人。本文所 採用且除非另有說明,否則術語“處理MD,,包括預防患者 之MD復發與/或延長MD患者保持緩解之時間。Elselvier, New York 1985). The terms "biohydrolyzable amidines and biohydrolyzable esters", "biohydrolyzable carbamates", "biohydrolyzable carbonate esters", unless otherwise stated, "," Biologically hydrolyzable ureas "and" Biohydrolyzable phosphates "refer to compounds such as amidine, esters, carbamates, carbonates, ureas, or phosphates. The compounds:丨) Does not interfere with the biological activity of the compound, but gives the compound beneficial in vivo properties, 々 Absorptivity, duration of action or start time of action; or 2) No biological activity: can be converted into biologically active compounds in vivo. Examples of biologically hydrolyzable compounds include (but are not limited to): low carbon number alkyl groups, low carbon number acid oxygen, alkyl alcohols (such as: ethyl acetate, ethyl acetate) , Aminocarbonyloxymethane :, Tentamyloxymethyl and Tentamyloxyethyl), lactone esters (such as: phthaloyl and: substituted phthaloyl esters), low-carbon alkoxyalkyloxyalkyl Esters (such as: methoxycarbonyloxy-ethoxyethoxyethyl and isopropoxycarbonyloxyethyl), alkoxyalkyl 89179 -34-200418455 esters, choline esters and amido alkyl esters (such as : Ethylaminomethyl). Examples of biohydrolyzable amidines include, but are not limited to, low carbon number alkylamidines, α-aminoacid amidines, alkoxyamidines, and alkylaminoalkylcarbonylamines. Examples of biohydrolyzable carbamates include, but are not limited to, low-carbon alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines With polyetheramines. Many selective cytokine inhibitory agents contain one or more palmar centers, and racemic or diastereomeric mixtures can occur. The invention includes the use of the pure stereoisomeric forms of these compounds and the use of mixtures of those forms. For example, mixtures of enantiomers containing equal or unequal amounts of selective cytokine inhibitory agents can be used in the methods and compositions of the invention. The purified (R) or (S) enantiomer of a clear compound disclosed herein may be substantially free of its other enantiomer. As used herein, and unless otherwise stated, the term "pure stereoisomerism" refers to one stereoisomer of a compound that includes substantially no other stereoisomer of the compound in the composition. For example, the pure stereoisomer composition of a compound with an opposing center is essentially free of the relative enantiomer of the compound. The pure stereoisomers of a compound with two palm centers are essentially free of other diastereomers of the compound. A typical pure stereoisomeric compound comprises about 80% by weight of one of the compounds and about 20% by weight of the compound, and more preferably about 90% by weight of the compound. A stereoisomer and other stereoisomers of the compound below about 10% by weight, even more preferably about 95% by weight of one of the compounds and about 5 weight 89179 -35- 200418455% of this compound Other stereoisomers of the compound. Most preferably, it is about 97% by weight or more of one of the stereoisomers of the compound and about 3% by weight or less of the other stereoisomers of the compound. As used herein and unless otherwise specified, the term "high stereoisomerism" refers to one of the stereoisomers of the compound that contains about 60% by weight or more, preferably about 70% by weight or more, and more preferably about One of the stereoisomers of the compound above 80% by weight. As used herein, and unless otherwise stated, the term "pure enantiomerism" refers to the pure stereoisomeric composition of a compound having one palm center. Similarly, "highly enantiomeric" refers to the highly stereoisomeric composition of a compound having an opposing center. It is understood that if the structural formula shown does not match the specified name, the structural formula presented will be the main one. In addition, if the stereochemistry or a part of the structural formula is not represented by, for example, a thick line or a dashed line, the structural formula or a part of the structural formula will include all of its stereoisomers. Second active agent The second active agent can be used in conjunction with a selective cytokine inhibitory agent in the methods and compositions of the present invention. In a preferred embodiment, the second active agent can inhibit or relieve the macula-damaged condition, produce an anti-angiogenic effect or an anti-inflammatory effect, or indeed make the patient comfortable. Examples of the second active agent include (but are not limited to): steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neutrophil factors, regulators of neovascularization, Anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds, anti-89179 -36- 200418455 vasomotor compounds, other agents known to inhibit or relieve MD symptoms, and their pharmaceutically acceptable salts and solvents Compounds, hydrates, stereoisomers, clathrates, prodrugs and pharmaceutically active metabolites. In some specific embodiments, the second active agent is phenanthrene, purlytin, angiostatic steroid, rhuFab, interferon-2α, or pentoxifylline. Examples of photosensitizers include ( But it is not limited to Fettfin, tin etiopurpurin and motexafin lutetium. Fitphen can be used to treat wet MD. Cour, M., et al. Drugs Aging 19: 101-133 (2002). Fitphen is a vascular blocking photoreactive dye that can be administered via injection. Examples of xanthine derivatives include, but are not limited to, pentoxifylline. Anti-VEGF antibodies include (but are not limited to): rhuFab. Examples of steroids include, but are not limited to, 9-Member-11,21-dihydroxy-16,17_1-methylethylenebis (oxy) pregnant-1,4-diene-3,20-dione. Examples of prostaglandin F2a derivatives include, but are not limited to: latanoprost (see U.S. Patent No. 6,225,348, the disclosure of which is fully incorporated herein by reference). Examples of antibiotics include (but are not limited to): tetracycline and its derivatives, rifamycin and its derivatives, macrolides and metronidazole (see US Patent Nos. 6,218,369 and 6,015,803, the disclosures of which have been Fully incorporated herein by reference). Examples of phytoestrogens include, but are not limited to: genistein, genistein, 6'-0-Mal genistein, 6'-0-Ac genistein, lignin isoflavones, daidzin, 6'_0_Mal daidzein, 6'-0-Ac soy taste, daidzein, glycidin, 6'-0-Mal daidzein, mesoflavone 89179 -37- 200418455 (biochanin) A, Formononetin and mixtures thereof (see US Patent No. 6,001,368, the disclosure of which is fully incorporated herein by reference). Examples of anti-inflammatory agents include, but are not limited to, triamcinolone and dexamethasone (see U.S. Patent No. 5,770,589, the disclosure of which is fully incorporated herein by reference). Anti-angiogenic compounds include (but are not limited to): thalidomide and selective cytokine inhibitory drugs (IMiDs ™, Celgene Corp., NJ). Examples of interferons include (but are not limited to): interference素 -2α. In another embodiment, the second active agent is glutathione (see U.S. Patent No. 5,632,984, the disclosure of which is fully incorporated herein by reference). Examples of growth hormones include (but are not limited to): basic fibroblast growth factor (bFGF) and transforming growth factor b (TGF_b). Examples of neutrophil factors include, but are not limited to, brain-derived neutrophil factors (BDNF). Examples of modulators of neoangiogenesis include, but are not limited to, fibrinogen activator type 2 (PAI-2). Other medicines that can be used to treat MD include (but are not limited to) EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and RETISERT implants (Bausch & Lomb Medicine 廒). Methods of treating prophylaxis The present invention includes methods of preventing, treating and / or treating a variety of MDs. -38- 89179 200418455 As used herein and unless otherwise exaggerated, M, π March, the term "prevention of MD,", "Treatment = and treatment of mediocrity, including (but not limited to) inhibiting or reducing one of _ related = The severity of the symptoms. Symptoms and related syndromes related to MD include (but limited to): the choroid of white-yellow gadolinium in the basement, discoid nodule tissue under the macula, the face of the pulse and even the veins ... the formation of pancreatic praying blood officers, retinal pigment epithelium. " Retinal pigment epithelium atrophy, long hemorrhage from the choroid (immediately below the retina rich vascular tissue layer), blurred vision or distorted vision, central blind spots, abnormal pigments, internal threads in the cloth A layer of fine-grained material is deposited and the Bruch film thickens and decreases permeability. As used herein, unless otherwise specified, the term "treating a woman" refers to the administration of a compound or other active agent of the present invention after the onset of symptoms of MD, where "prevention" refers to Patients at risk of MD) Administration. Patients at risk of MD "Examples of patients include (but are not limited to): seniors over 60 years of age and patients suffering from (but not limited to) · diabetes and leprosy (eg enl) Patients with a family history of MD are also good candidates for preventive therapy. As used herein and unless otherwise stated, the term "treating MD, including preventing MD recurrence and / or prolonging MD patients to maintain remission, is used." time.
本發明包括對罹換不同階段及特定疾病型態之患者治 療、預防與處理MD及相關症狀之方法,該疾病包括(但不 限於):彼等稱為乾型MD、濕SMD、與老化有關之黃斑變 性(ARM)、脈絡膜新血管形成(CNVM)、視網膜色素上皮剥 離(PED)及視網膜色素上皮萎縮(RPE)。其進一步包括治療 過去曾治療MD但對標準藥物及不以藥物為主之md治療法 沒有反應之患者及過去未曾接受MD治療之患者。由於MD 89179 -39- 200418455 患者具有多種不同臨床症狀及多種不同臨床結果,因此對 患者之治療法可隨其癒後而異。習此相關技藝之臨床專家 不需過分實驗即可決定特定之第二藥劑及可用於有效治療 個別患者之治療法。 本發明涵括之方法包括對已罹患或容易罹患MD之患者 投予一種或多種選擇性細胞激素抑制性藥劑或其醫藥上可 接受之鹽類、溶劑化物、水合物、立體異構物、籠形包合 物或前藥。 本發明之一項具體實施例中,選擇性細胞激素抑制性藥 劑之建議每日劑量範圍約1 mg至約1〇,〇〇〇 mg,可呈單一劑量 一天投藥一次,或最好分成小劑量在一天内投藥。更明確 言之’可將一天劑量分成兩等分在一天内投藥兩次。明確 之每曰劑量範圍為約1 mg至約5,〇〇〇 mg/天,約1〇 mg至約 2,500 mg/天,約 1〇〇 mg至約 8〇〇 mg/天,約 1〇〇 mg至約[Mo 邮/ 天,或約25 mg至約2,500 mg/天。處理患者時,該療法先使 用較低劑量,可能約1 mg至約2,500 mg,若需要時再提高至 約200 mg至約5,000 mg/天,依患者之整體反應而定,可呈單 一劑量投藥,或分成小劑量投藥。特定具體實施例中,弘(3,4_ 二甲氧基-苯基)-3-(1-氧代-1,3-二氫-異吲哚基)_丙醯胺之 投藥量為每天 400、800、1,200、2,500、5,000或 1〇,000 mg,分 兩次投藥。該治療法可持續約2至約2〇週,約4至約丨6週,約 8至約12週,直到達成所需效果為止或可慢性維持所需效果 為止。 |用第二活性劑之組合_法 89179 -40- 200418455 、本發以Μ方法包括投予選擇性細胞激素抑制性藥劑 或藥上可接文之鹽類、溶劑化物、水合物、立體異構 物i元巴口物或㈤樂,併用第二活性劑或活性成分。選 擇性細胞激素抑制性藥南余 _ 、 条釗貝例揭7F於本又中(參見例如:第 4.1即);及第二活性劑實例亦揭示於本文中(參見例如:第 4 · 2 節)。 才又予患者之選擇性細胞激素抑制性藥劑與視需要選用之 第二活性劑成分可依相同或相異途徑同時或依序投藥。對 特足活性劑所使用特定投藥途徑之適宜性端賴活性劑本身 (例如·其疋否可在進入血流之前不需分解即可經口投藥) 與所治療之疾病而定。投予選擇性細胞激素抑制性藥劑之 較佳途徑為經口或經眼睛投藥。本發明第二活性劑之較佳 投樂途徑係習此相關技藝之人士已知者。參見例如:The present invention includes methods for treating, preventing, and managing MD and related symptoms for patients suffering from different stages and specific disease patterns. The disease includes (but is not limited to): they are called dry MD, wet SMD, and related to aging. Macular degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelium detachment (PED), and retinal pigment epithelial atrophy (RPE). It further includes treating patients who have previously treated MD but have not responded to standard drugs and non-drug-based md treatments and patients who have not received MD treatment in the past. Because MD 89179 -39- 200418455 patients have many different clinical symptoms and many different clinical results, the treatment of patients may be different from time to time. Clinical experts who are familiar with this technology can determine specific secondary agents and treatments that can be used to effectively treat individual patients without undue experimentation. The methods encompassed by the present invention include administering one or more selective cytokine inhibitory agents or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, Shaped inclusion compound or prodrug. In a specific embodiment of the present invention, the recommended daily dose range of the selective cytokine inhibitory agent is about 1 mg to about 10,000 mg, which can be administered once a day in a single dose, or preferably divided into small doses Dosing in one day. More specifically, 'a day's dose can be divided into two equal portions and administered twice a day. The specific dosage range is about 1 mg to about 5,000 mg / day, about 10 mg to about 2,500 mg / day, about 100 mg to about 800 mg / day, and about 100 mg. mg to about [Mo post / day, or about 25 mg to about 2,500 mg / day. When treating patients, the therapy is first administered at a lower dose, which may be about 1 mg to about 2,500 mg, and if required, increased to about 200 mg to about 5,000 mg / day, which can be administered in a single dose, depending on the overall response of the patient , Or divided into small doses. In a specific embodiment, the dosage of Hong (3,4_dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindolyl) _propanamide is 400 per day , 800, 1,200, 2,500, 5,000 or 10,000 mg, divided into two doses. The treatment can last from about 2 to about 20 weeks, from about 4 to about 6 weeks, and from about 8 to about 12 weeks, until the desired effect is achieved or the desired effect can be maintained chronically. | Combination with a second active agent_ 法 89179 -40- 200418455, the method of the present invention includes the administration of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomerism物 i 元 口 口 物 or ㈤ 乐 and use a second active agent or active ingredient. Selective cytokine inhibitory drugs Nan Yu, Tiao Zhaobei 7F is disclosed in this book (see, for example, Section 4.1); and an example of a second active agent is also disclosed in this article (see, for example, Section 4 · 2 ). The selective cytokine inhibitory agent and the second active agent component selected as needed can be administered to the patient simultaneously or sequentially according to the same or different routes. The appropriateness of the particular route of administration of the full-featured active agent depends on the active agent itself (eg, whether it can be administered orally without decomposition before entering the bloodstream) and the disease being treated. The preferred route of administration of a selective cytokine inhibitory agent is oral or ocular administration. The preferred method of entertaining the second active agent of the present invention is known to those skilled in the art. See for example:
Physicians’ Desk Reference (第 57版,2003)。 在一項具體實施例中,第二活性劑係經口、靜脈内、肌 内、皮下、經黏膜、局部或穿皮式,每天投藥一或兩次, 用量為約1 mg至約2,500 mg,約1 mg至約2,000 mg,約10 mg 至約 1,500 mg,約 50 mg至約 1,000 mg,約 100 mg至約 750 mg, 或約250 mg至約500 mg。 另一項具體實施例中,第二活性劑係每週、每月、每兩 個月或每年投藥一次。其他活性劑之明確劑量依所使用之 特定藥劑,所治療或預防之MD型態,MD之嚴重性與階段 及患者目前使用之選擇性細胞激素抑制性藥劑與任何視需 要選用之其他藥劑之用量而定。特定具體實施例中,第二 89179 -41 - 200418455 :性劑為類固醇、光敏化劑、整合素、抗氧化劑、干擾素、 黃口票呤素衍生物、生長激素、趨中性白血球因+、新血管 禾成作用之㉟節劑、抗_VEGF抗體、前列腺素、抗生素、植 物雌激素/肖火化合物或抗血管擴增化合物,或其組合。 f術干預法 本毛月包括一種治療、預防與/或處理MD之方法,其包括 才又予&擇性細胞激素抑制性藥劑或其醫藥上可接受之鹽 彳化物、水合物、立體異構物、籠形包合物或前藥, 併:(例如·在之前、期間或之後)手術干預法。手術干預 法,、例括(但不限於)光或雷射療法、放射療法,視網膜色 素上皮移植與網膜中心移位。 k擇性細胞激素抑制⑲藥劑與手術干法之、组合用法提 t、獨特之療& ’可為某些患者帶來令人意想不到之效果。 在不受理論限制下,咸信選擇性細胞激素抑制性藥劑當與 手術干預法併行時,可提供加成或促效之效果。 ” 月確《具體貫施例中,本發明包括治療、預防與/或處理 MD《万法’其包括對有此需要之患者投予有效量之選擇性 細胞激素抑制性藥劑或其醫藥上可接受之鹽類、溶劑化 2水口物、立體異構物、籠形包合物或前藥,併用光或 田射療法。光或雷射療法實例包括(但不限於):雷射光致 凝結療法或光動力療法。 元敌 4擇性細胞激素抑制性藥劑可與手術干預法同時或依序 進行。—項具體實施例中,選擇性細胞激素抑制性藥 光或雷射療法之前進行。另-項具體實施例中,選擇性細 89179 -42- 200418455 击"性藥劑係在光或雷射療法之後進行。-項具體 二=選擇性細胞激素抑制性藥劑係在光或雷射療法 :固二、仃。化合物可在雷射手術至少四週前、兩週前、一 =或即將手術前或手術同時或手術後投藥,共治療约 上2 ** 16週。 二具體實施例中,本發明之預防劑或治療劑係循環投 者。循環療法涉及首先投予藥劑一段時間後,投予該 藥背彳與/或第二藥,】一段车 牙 条奴時間,並重覆此連續投藥過程。循 :甘“可降低其對一種或多種療法發展出抗性,避免或降 低八中—種療法之副作用,與/或改善治療效果。 :確,具體實施例中’預防劑或治療劑係循環投藥約6 =休Γ約1或2次。一個循環可包括投予治療劑或預防 或^。循環投藥之次數可能約1至㈣個循 、、’、土、、々1〇個循環,或約2至約8個循環。 合物與單一嚴位劍唢 醫藥組合物可呈個別單一單位劑型使用。本發 =物與劑型包括選擇性細胞激素抑制性藥 ::二鹽類太溶劑化物、水合物、立體異構物、籠;包 二:或則樂。本發明醫藥組合物與劑型可 種賦形劑。 但4夕 本發明醫藥組合物與劑型亦可包含—種或多種其他活性 蜊。因此,本發明醫藥組合物與劑型包含 性劑(例如:選擇性細胞激素抑制性藥劑或其醫藥:;二 89179 -43- 200418455 H溶劑化物、水合物、立體異構物 前藥與第二活性劑)。視需要選用之复他、、舌性:“物或 所揭示(參見例如:第42節)。 …性蜊貫例如本文 本發明之單—單位劑型適合經口、黏膜(例如:鲁、 陰道、頰内或直腸)或非經腸式(例⑹:皮下、靜:、:下大 丸樂注射、肌内或經動脈内)、局 ‘ 、巧如•眼樂水)、經眼 、::皮式或經皮膚投藥給患者。劑型實例包括(但不限 嫉w η人 切性明膠囊;扁囊劑; 疋§錠;勻散液;栓劑;粉劑;氣霧劑(例如··鼻 口貧視或吸人劑);眼藥水;凝膠;適合經口或黏膜投給患者 之液體劑型’包括懸浮液(例如:水性或非水性液體縣浮 液:水包練乳液或油包水性乳液)、溶液與驰劑;適合非 經腸式投藥給患者之液體劑型;與無菌固體(例如:結晶或 非晶型固體),其可再組成適合非經腸式投藥給患者之液體 劑型。 本發明劑型之組成、形狀與種類主要依其用途而定。例 如:用於急性治療之劑型可包含一種或多種活性劑,其含 量則高於用於慢性治療相同疾病之劑型中之含量。同樣 地,非經腸式劑型中一種或多種活性劑之含量可低於用於 治療相同疾病之口服劑型中之含量。本發明所涵括明確劑 型之此等及其他方式之差異係習此相關技藝之人士咸了解 者。參見例如·· Remington’s Pharmaceutical Sciences,18th ed. Mack Publishing,Easton PA (1990)。 典型之醫藥組合物與劑型包含一種或多種賦形劑。合適 89179 -44 - 200418455 之賦形劑係習此藥學技藝之人士習知者,合適之賦形劑之 不設限實例係本文所提供者。特定之賦形劑是否適合加至 醫藥組合物或劑型中,端賴相關技藝已知之多種因素而 定,包括(但不限於)劑型投藥給患者之方式。例如:如錠 劑之口服劑型所包含之賦形劑可能不適用於非經腸式劑 型。特定賦形劑之適宜性亦依劑型中明確活性劑而定。例 如:有些活性劑可因一些賦形劑(如:乳糖),或當曝露到 水時,可加速降解。包含一級或二級胺之活性劑特別容易 受到此等加速降解作用。因此,本發明包括之醫藥組合物 與劑型中除了單醣或雙醣外,可能包含(若包含時)少量乳 糖。本文所採用術語“無乳糖”意指若可能包含之任何乳糖 量不足以實質上提高活性劑之降解率。 本發明無乳糖組合物可包含相關技藝習知之賦形劑,其 示於美國藥典(U.S.Pharmacopeia)(USP)25-NF20 (2002)中。一 般而言,無乳糖組合物包含醫藥上可相容且醫藥上可接受 之含量之活性劑、結合劑/填料、與潤滑劑。較佳無乳糖劑 型包含活性劑、微晶纖維素、預糊化澱粉與硬脂酸鎂。 本發明尚包括包含活性劑之無水醫藥組合物與劑型,因 為水會促使某些化合物降解。例如··添加水(例如:5%)係 醫藥技藝上廣泛接受用於模擬長期儲存狀態之一種方式, 以測定調配物之貨架壽命或安定性隨時間之變化。參見例 如:Jens T. Carstensen,Drug Stability ·· Principles & Practice, 2d. Ed·,Marcel Dekker,NY,NY,1995, pp. 379-80。實際上,水與熱 會加速某些化合物降解。因此,水對調配物之影響非常重 -45- 89179 200418455 要’因為調配物之製造、操作、句奘 、两加丄 a t 储存、運送盥使用 匕‘中經常會遇到水分與/或濕度。 〃 本I明之典水醫藥組合物與劑型、 夕士 A 土 J ^用播水或低水含量 心成刀及低水分與低濕度之條件邀 中 “午I備醫樂組合物與劑型 3讀與至少-種包含—級或二級胺之活性劑時,若 二=在製造、包裝與/或儲存期間實f上會遇到水分時,最 好呈無水型。 無水醫藥組合物之製備與儲#應保持其無水性質。因 二無水組合物最好使用已知可防水之材料包裝,以使其 限二括在週當調配物之套组中。合適之包裝實例包括(但不 七封m、塑膠、單位劑量容器(例 泡包與長條包。 )知 =發明尚,括包含—種或多種可降低活性劑降解速度之 心物《醫樂組合物與劑型。此等化合物在本文中稱為“安 包括(但不限於):抗氧化劑,如··抗壞血酸、pH緩 衝劑或鹽類緩衝劑。 如同賦形劑之用量與種類’劑型中活性劑之用量與明確 種類可能依如,例如· 々 、 3 ·叙丁患者 < 途徑等因素變化。然而, 本發明之典型杳丨丨刑4人 # 、 土匕§選擇性細胞激素抑制性藥劑或其醫 樂上可接受之_ % 、、、 风九、落劑化物、水合物、立體異構物、籠 形包合物或前藥,复田 /、用!為約1至約10,000 mg。典型劑型包 含選擇性細胞激II 〃 、、、 素抑制性藥劑或其醫藥上可接受之鹽類、 溶劑化物、水合物 、 乂體異構物、龍形包合物或前藥,其 含量為約卜2、5、! n q 10、25、50、100、200、400、800、1,200、 89179 -46- 200418455 2,500、5,000或10,000mg。特定具體實施例,較佳劑型包含 3-(3,4-二甲氧基·苯基)-3-(1-氧代-1,3-二氫-異吲哚-2-基丙 醯胺,其含量為約400、800或1,200 mg。典型劑型包含第二 活性劑,其含量為約1至約2,500 mg,約1 mg至約2,000 mg, 約 10 mg至約 1,500 mg,約 50 mg至約 1,000 mg,約 100 mg至約 750 mg,或約250 mg至約500 mg。當然,第二活性劑之明確 用量將依所使用之明確藥劑、所治療或處理之MD型態及選 擇性細胞激素抑制性藥劑與併行投藥給患者之任何其他視 需要選用之活性劑之用量而異。 口月良劑型 適合口服之本發明醫藥組合物可呈分離之劑型,如(但不 限於)··錠劑(例如:口嚼錠)、膜衣錠、膠囊與液體(例如: 加味糖漿)。此等劑型包含預定量之活性劑,可依習此藥學 技藝之人士已知之方法製備。一般參見Remington’s Pharmaceutical Sciences,18th ed·,Mack Publishing,Easton PA (1990)。 典型之口服劑型之製法係由活性劑與至少一種賦形劑, 依據習知之醫藥化合技術均勻混合。賦形劑可呈多種型 式,端賴所需投藥之製劑型式而定。例如··適用於口服液 體或氣霧劑之賦形劑包括(但不限於):水、甘醇、油類、 醇類、調味劑、防腐劑與著色劑。適用於固體口服劑型(例 如:粉劑、錠劑、膠囊與膜衣錠)之賦形劑實例包括(但不 限於):澱粉、糖類、微晶纖維素、稀釋劑、製粒劑、潤滑 劑、結合劑與崩解劑。 -47- 89179 200418455 由於錠劑與膠囊方便投藥,因此代表最有利之口服單位 劑型,此時則使用固體賦形劑。若需要時,錠劑可依標準 水性或非水性技術包覆包衣。此等劑型可依任何藥學方法 製備。通常,醫藥組合物與劑型之製法為均勻混合活性劑 與液體載劑、均勻分散之固體載劑或兩者,然後若必要時, 使產物形成所需製劑。 例如:錠劑之製法可壓縮或模鑄。壓縮錠劑之製法為於 合適機器中,壓縮自由流動形式之活性劑形如:粉末或顆 粒,可視需要與賦形劑混合。模鑄錠劑之製法為於合適機 器中,使粉狀化合物經惰性液態稀釋劑濕化。 可用於本發明口服劑型之賦形劑包括(但不限於)··結合 劑、填料、崩解劑與潤滑劑。適用於醫藥組合物與劑型之 結合劑包括(但不限於)··玉米澱粉、馬鈴薯澱粉或其他澱 粉、明膠、天然膠質與合成膠質,如··金合歡膠、藻酸鈉、 藻酸、其他藻酸鹽、粉末狀黃耆膠、關華豆膠、纖維素與 其衍生物(例如··乙基纖維素、纖維素乙酸酯、羧甲基纖維 素鈣、羧甲基纖維素鈉)、聚乙婦吡咯啶酮、甲基纖維素、 預糊化澱粉、羥丙基甲基纖維素(例如·· nos. 2208、2906、 2910)、微晶纖維素與其混合物。 微晶纖維素之合適形式包括(但不限於)以AVICEL-PH-101 、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105名稱出 售之材料(來自 FMC公司,American Viscose Division,Avicel Sales,Marcus Hook, PA)與其混合物。明確之結合劑為微晶纖 維素與羧甲基纖維素鈉之混合物,其係以AVICEL RC-581之 -48· 89179 200418455 名稱出售。合適之盔永式M 人 …尺戍低水分賦形劑或添加物包括 AVICEL_PH_l〇3TM與澱粉 15〇〇 LM。 適用於本文所揭示醫藥組合物與劑型之填料實例包括 (但不限於).滑石、碳酸㊣(例如:顆粒或粉末);微晶纖維 素、纖維素粉末、葡聚糖、高嶺土、甘露糖醇、石夕酸、山 梨糖醇、澱粉、預糊化澱粉與其混合物。本發明醫藥組合 物中結合劑或填料之典型含量占醫藥組合物或劑型重量之 約50至約99重量%。 /發明組合物中使用崩解劑所形成之錠劑#曝露到水性 :境時,即會崩解。包含太多崩解劑之錠劑可能於儲存時 崩解丄而含量太少時,則可能無法依所需速率或在所需條 件下崩解。因此崩解劑之量應足夠,不可太多或太少,以 免負$改變本發明固體口服劑型形成時所使用活性劑之釋 出崩解劑之用量隨調配物型態變化,其係習此相關技藝 =人士容易了解者。典型之醫藥組合物包含約0.5至約15重 量%崩解劑,以約丨至約5重量。/()崩解劑較佳。 本發明醫藥組合物與劑型可使用之崩解劑包括(但不限 於)·洋菜、藻酸、碳酸鈣、微晶纖維素、交聯羧甲基纖維 素鈉、聚乙烯吡咯啶酮、普卡啉(poiacrilin)_、澱粉乙醇酸 鈉馬給薯或樹薯澱粉、其他澱粉、預糊化澱粉、其他澱 粉、黏土、其他藻酸、其他纖維素、膠質與其混合物。 本發明醫藥組合物與劑型中可使用之潤滑劑包括(但不 限於):硬脂酸鈣、硬脂酸鎂、礦物油、輕礦物油、甘油、 山梨糖醇、甘露糖醇、聚乙二醇、其他二醇類、硬脂酸、 89179 -49- 200418455 月桂基硫酸酯鈉、滑石、氫化植物油(例如:花生油、棉籽 油、葵花油、芝麻油、橄欖油、玉米油與大豆油)、硬脂酸 鋅、油酸乙酯、月桂酸乙酯、洋菜與其混合物。其他潤滑 劑包括例如:矽酸鹽矽膠(AEROSIL200,由W.R· Grace Co., Baltimore,MD製造)、合成矽石之凝結氣霧劑(由Degussa c〇. of Piano, TX出售)、CAB_〇_SIL (熱解之二氧化矽產品,由Cab〇t Co· of Boston,ΜΑ出售)與其混合物。若使用時,潤滑劑之典 型用里低於醫樂組合物或劑型重量之約1 %。 本發明之較佳固體口服劑型包含選擇性細胞激素抑制性 藥劑、無水乳糖、微晶纖維素、聚乙晞吡咯啶酮、硬脂酸、 膠體無水石夕石與明膠。 緩釋杳丨却 伞贫明活性劑Physicians ’Desk Reference (57th edition, 2003). In a specific embodiment, the second active agent is administered orally, intravenously, intramuscularly, subcutaneously, transmucosally, topically or transdermally, once or twice daily, in an amount of about 1 mg to about 2,500 mg, About 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg. In another embodiment, the second active agent is administered weekly, monthly, every two months, or annually. The specific dosage of other active agents depends on the specific agent used, the type of MD being treated or prevented, the severity and stage of MD, and the amount of selective cytokine inhibitory agent currently used by the patient and any other agent selected as needed It depends. In a specific embodiment, the second 89179-41-200418455: the sex agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthomone derivative, a growth hormone, a neutrophil +, Neovascular effects, tinctures, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens / Xiaohuo compounds or anti-angiogenic compounds, or combinations thereof. f. Surgical intervention method This hair month includes a method for the treatment, prevention and / or treatment of MD, which includes administering & selective cytokine inhibitory agent or a pharmaceutically acceptable salt thereof, hydrate, sterol Structures, clathrates or prodrugs, and: (e.g., before, during, or after) surgical interventions. Surgical intervention methods, including (but not limited to) light or laser therapy, radiation therapy, retinal pigment epithelial transplantation and omental center displacement. Selective cytokine inhibition, medicaments and surgical methods, combined use, unique treatments & 'can bring unexpected results to some patients. Without being limited by theory, the salt-selective cytokine inhibitory agent can provide an additive or pro-active effect in parallel with surgical intervention. "In the specific embodiments, the present invention includes the treatment, prevention, and / or treatment of MD" Wanfa, "which includes administering an effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable drug to a patient in need thereof. Accepted salts, solvated sprues, stereoisomers, clathrates or prodrugs, and use light or field therapy. Examples of light or laser therapy include (but are not limited to): laser photocoagulation therapy Or photodynamic therapy. Yuandi 4 selective cytokine inhibitory agents can be performed simultaneously or sequentially with surgical intervention.-In a specific embodiment, selective cytokine inhibitory drugs are performed before light or laser therapy. Another- In the specific embodiment, the selectivity is 89179 -42- 200418455. The sex agent is performed after light or laser therapy.-Item specific two = selective cytokine inhibitory agent is under light or laser therapy: solid 2. 仃. Compounds can be administered at least four weeks before, two weeks before, one = or immediately before surgery or at the same time or after surgery, for a total of about 2 ** 16 weeks. In two specific embodiments, the present invention Preventive or cure The agent is a cyclic agent. Circulation therapy involves first administering the medicament for a period of time and then administering the drug to the back and / or the second medicament,] a period of car teeth slave time, and repeating this continuous administration process. Reduce its development resistance to one or more therapies, avoid or reduce the side effects of the eight middle therapy, and / or improve the therapeutic effect. : Indeed, in the specific embodiment, the 'prophylactic or therapeutic agent is administered cyclically for about 6 = about 1 or 2 times. One cycle may include the administration of a therapeutic agent or a prophylactic or prophylactic. The number of cyclic administration may be about 1 to ㈣ cycles, ′, 、, 土, 々 10 cycles, or about 2 to about 8 cycles. Compound and a single stern cymbal medicine composition can be used in individual single unit dosage forms. The present substance and dosage forms include selective cytokine inhibitory drugs :: di-salts too solvates, hydrates, stereoisomers, cages; package two: or Zele. The pharmaceutical composition and dosage form of the present invention can be used as excipients. However, the pharmaceutical compositions and dosage forms of the present invention may also include one or more other active clams. Therefore, the pharmaceutical composition and dosage form of the present invention include sexual agents (for example, selective cytokine inhibitory agents or their medicines; II 89179 -43- 200418455 H solvate, hydrate, stereoisomer prodrug and second activity剂). If necessary, select other, tongue: "the thing or the revealed (see for example: Section 42). ... sex clams such as the single invention of this text-unit dosage form suitable for oral, mucosal (such as: Lu, vagina, Intrabuccal or rectal) or parenteral (example: subcutaneous, static:,: Shimo Daimaru injection, intramuscular or intraarterial), bureau ', Qiaoru • eye music water), transocular, :: skin It can be administered to patients in a transdermal or transdermal manner. Examples of dosage forms include (but not limited to 人 人人 切 性 明 胶囊; a cachet; 锭 § tablets; a homogeneous solution; suppositories; powders; aerosols (such as ... Visual or inhalant); eye drops; gels; liquid dosage forms' including suspensions suitable for oral or mucosal administration to patients (for example: aqueous or non-aqueous liquid county suspensions: water-in-water emulsions or water-in-oil emulsions) Liquid solutions suitable for parenteral administration to patients; and sterile solids (such as crystalline or amorphous solids), which can be reconstituted into liquid dosage forms suitable for parenteral administration to patients. The composition, shape and type of the dosage form mainly depend on its use. For example: A dosage form for acute treatment may contain one or more active agents, the content of which is higher than the dosage form used for chronic treatment of the same disease. Similarly, the content of one or more active agents in parenteral dosage forms may be lower than that used. The content in oral dosage forms for the treatment of the same disease. The differences in these and other means included in the present invention are clearly understood by those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed. Mack Publishing , Easton PA (1990). Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients 89179 -44-200418455 are those skilled in the art of pharmaceuticals and suitable excipients. Examples of limitations are provided herein. Whether a particular excipient is suitable for addition to a pharmaceutical composition or dosage form depends on a number of factors known in the relevant art, including (but not limited to) the manner in which the dosage form is administered to the patient. For example : Excipients contained in oral dosage forms such as lozenges may not be suitable for parenteral dosage forms. The suitability of specific excipients also depends on the dosage form It depends on the active agent. For example, some active agents can be accelerated by some excipients (such as lactose) or can be accelerated when exposed to water. Active agents containing primary or secondary amines are particularly vulnerable to such accelerated degradation. Therefore, in addition to the monosaccharides or disaccharides, the pharmaceutical compositions and dosage forms included in the present invention may contain (if included) a small amount of lactose. As used herein, the term "lactose-free" means if any lactose may be contained in an insufficient amount To substantially increase the degradation rate of the active agent. The lactose-free composition of the present invention may include excipients known in the related art, which are shown in US Pharmacopeia (USP) 25-NF20 (2002). Generally speaking, The lactose-free composition comprises a pharmaceutically compatible and pharmaceutically acceptable content of an active agent, a binding agent / filler, and a lubricant. Preferred lactose-free dosage forms include the active agent, microcrystalline cellulose, pregelatinized starch, and magnesium stearate. The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing active agents because water can cause the degradation of certain compounds. For example, the addition of water (eg: 5%) is a method widely accepted in medical technology for simulating long-term storage conditions to determine the shelf life or stability of formulations over time. See, for example, Jens T. Carstensen, Drug Stability Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat can accelerate the degradation of certain compounds. Therefore, the effect of water on the formulation is very serious -45- 89179 200418455 It is because of the manufacture, operation, sentence, and two plus of the formulation that the storage and transportation of toilets are often encountered with moisture and / or humidity.典 The Code of Water Pharmaceutical Compositions and Dosage Forms of the Ming Dynasty, Xi Shi A Tu J ^ The conditions of sowing with water or low water content to make a knife and the conditions of low moisture and low humidity are invited to "Medical Preparations and Dosage Forms of Medical Preparations at Noon 3" In the case of at least one active agent containing a secondary or secondary amine, if two = water will be encountered during manufacturing, packaging, and / or storage, it is preferably an anhydrous form. Preparation of anhydrous pharmaceutical compositions and Storage # should maintain its anhydrous nature. Because the anhydrous composition is best packaged with a material that is known to be waterproof, so that it is limited to the set of weekly formulations. Examples of suitable packaging include (but not seven seals) m. Plastic, unit-dose containers (such as blister packs and long packs). Known = inventions, including one or more kinds of medical substances that can reduce the degradation rate of the active agent "medical composition and dosage forms. These compounds are described herein. It is called "Ann includes (but is not limited to): antioxidants, such as ... ascorbic acid, pH buffer or salt buffer. As the amount and type of excipients, the dosage and specific types of active agents in the dosage form may depend on , Such as · 々, 3 · Suding patients < Factors and other factors. However, the typical example of the present invention is: 刑 丨 # 4 人 #, 匕 §Selective cytokine inhibitory agent or its medically acceptable _%, ,, wind nine, drop agent, hydration Compounds, stereoisomers, clathrates, or prodrugs, which are used for reinstatement, about 1 to about 10,000 mg. Typical dosage forms include selective cytokines II 〃, 、,, or pharmacological inhibitors Acceptable salts, solvates, hydrates, corpus isomers, dragon-shaped inclusion compounds or prodrugs, the content of which is about 2, 5 ,! nq 10, 25, 50, 100, 200, 400, 800, 1,200, 89179 -46- 200418455 2,500, 5,000, or 10,000 mg. In specific embodiments, preferred dosage forms include 3- (3,4-dimethoxy · phenyl) -3- (1-oxo -1,3-dihydro-isoindole-2-ylpropanamine, which is present at a level of about 400, 800 or 1,200 mg. A typical dosage form contains a second active agent at a level of about 1 to about 2,500 mg, About 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg. Of course, the second activity Of The exact dosage will vary depending on the specific medicament used, the type of MD being treated or treated, and the selective cytokine inhibitory medicament, and the amount of any other active agent selected for concurrent administration to the patient as needed. The pharmaceutical composition of the present invention for oral administration may be in separate dosage forms, such as (but not limited to) ... lozenges (eg, chewable tablets), film-coated tablets, capsules, and liquids (eg, flavored syrup). These dosage forms include predetermined The amount of active agent can be prepared according to methods known to those skilled in the art of pharmacy. See generally Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990). A typical oral dosage form is prepared by uniformly mixing an active agent and at least one excipient according to a conventional pharmaceutical compounding technique. Excipients can take many forms, depending on the type of formulation required. For example, excipients suitable for oral liquids or aerosols include (but are not limited to): water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for solid oral dosage forms (such as powders, lozenges, capsules and film-coated tablets) include (but are not limited to): starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, Binders and disintegrants. -47- 89179 200418455 Because tablets and capsules are convenient for administration, they represent the most advantageous oral unit dosage form. In this case, solid excipients are used. If necessary, the tablets can be coated with standard aqueous or non-aqueous techniques. These dosage forms can be prepared by any pharmaceutical method. Generally, pharmaceutical compositions and dosage forms are prepared by uniformly mixing the active agent with a liquid carrier, a uniformly dispersed solid carrier, or both, and then, if necessary, forming the product into a desired formulation. For example, the method of making pastilles can be compressed or die-cast. Compressed tablets are prepared in a suitable machine by compressing the active agent in a free-flowing form, such as powder or granules, and mixing it with excipients as needed. Moulded ingots are prepared by moistening powdered compounds with an inert liquid diluent in a suitable machine. Excipients that can be used in the oral dosage form of the present invention include, but are not limited to, a binding agent, a filler, a disintegrant, and a lubricant. Suitable binding agents for pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural gums and synthetic gums, such as acacia gum, sodium alginate, alginic acid, others Alginate, powdered tragacanth, guanhua bean gum, cellulose and its derivatives (e.g. ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), Polyethylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (eg, · nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold under the names AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. The clear binding agent is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, which is sold under the name -48 · 89179 200418455 of AVICEL RC-581. Suitable helmets for permanent M people ... Low-moisture excipients or additives include AVICEL_PH_103 and starch 150 LM. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, rhenium carbonate (eg, granules or powder); microcrystalline cellulose, cellulose powder, dextran, kaolin, mannitol , Oxalic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. A typical content of the binder or filler in the pharmaceutical composition of the present invention is about 50 to about 99% by weight based on the weight of the pharmaceutical composition or dosage form. / The tablet # formed by using a disintegrant in the composition of the invention will disintegrate when exposed to an aqueous environment. Lozenges containing too much disintegrant may disintegrate during storage and too little, and may not disintegrate at the required rate or under the required conditions. Therefore, the amount of the disintegrant should be sufficient, not too much or too little, so as not to change the amount of the disintegrant that is used in the formation of the solid oral dosage form of the present invention. Related skills = easy to understand. A typical pharmaceutical composition contains from about 0.5 to about 15% by weight of a disintegrant, and from about 5 to about 5% by weight. / () Disintegrant is preferred. Disintegrating agents that can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, general Carboline (poiacrilin), sodium starch glycolate, potato or cassava starch, other starch, pregelatinized starch, other starch, clay, other alginic acid, other cellulose, gum and mixtures thereof. Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include (but are not limited to): calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol Alcohols, other glycols, stearic acid, 89179 -49- 200418455 sodium lauryl sulfate, talc, hydrogenated vegetable oils (for example: peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), hard Zinc stearate, ethyl oleate, ethyl laurate, agar and mixtures thereof. Other lubricants include, for example: Silicate Silicone (AEROSIL 200, manufactured by WR Grace Co., Baltimore, MD), Condensing Aerosols of Synthetic Silica (sold by Degussa Co. of Piano, TX), CAB SIL (pyrolytic silica product, sold by Cabot of Boston, MA) and mixtures thereof. When used, lubricants are typically used at less than about 1% by weight of the medical composition or dosage form. The preferred solid oral dosage form of the present invention includes a selective cytokine inhibitory agent, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous stone stone and gelatin. Sustained release
、 …〜Μ剛仅朁乏人士習知之控制I 出方式或傳送裝置投藥。丨實例包括(但丨限於):彼等言 明於美國專利案號:3,845,770 ; 3,916,899 ; 3,536,8〇9 : =^與4澤,719、5,674,533、5 ()59,595、5,591,767 一’ ^’548、5,073,543、5,639,476、5,354,556與 5,733,566,其泰 =谷,=丨用之!式完全併入本文中。此等劑型可❹ 膜、渗透系統、多層包衣、微粒;1母質、凝膠、㈣ 組合’用於提供緩釋或控制釋放 微小球《 供不同比例之所需釋放圖形。習 ^種活性劑’可摘 適之控制釋出調配物(包括本 目_關技蟄之人士已知洽 明活性劑選擇使用。本發明因此涵:=)很容易配合“ 括可控制釋出之適合口 89179 -50· 200418455 服投藥之單一單位劑型如 囊(gelcaps)與膜衣錠。 (但不限於)鍵劑 膠囊、明膠 所有控制釋出之醫藥產品均有一 未控制釋出之對等物之藥㈣效其 使用<最佳設計之控制釋出製:療法所 括延長藥物活性、降低投藥頻率及提高患者適庶性。=包 ,制,出之調配物可用於影㈣用開始時間或其他特性,’ 口.樂物《血中濃度,因此可影響副 用)之發生。 小艮田丨J作 大多數控制釋出調配物之設計為先釋出— 性船,促使產生所需治療效果1後逐漸連續釋:其他(量舌 之樂物’以維持此治療或預防有效量之藥物—段時間。為 了在體内維持此藥物之μ量,劑型中釋出藥物之速率必 須可置換藥物在體内代謝及排出之速率。活性劑之控制釋 出可受到多種條件刺激,包括(但不限於):ρΗ、溫度、酵 素、水或其他生理條件或化合物。 非經腸式剑外 非經腸式劑型可依多種不同途徑投予患者,包括(但不限 於)··玻璃體内、皮下、靜脈内(包括大丸劑注射)、肌内與 動脈内。由於其投藥法主要繞過患者對抗外來物之天然防 禦系統,因此非經腸式劑型最好為無菌或可在投予患者之 前先殺菌。非經腸式劑型實例包括(但不限於)··現成可用 於注射之溶液,現成可用於溶解或懸浮於醫藥上可接受之 89179 -51- 200418455 注射用媒劑之乾物產品、現成可注射用之懸浮液、與乳液。 可用於提供本發明非經腸式劑型之合適媒劑係習此相關 技藝之人士習知者。其實例包括(但不限於):注射用水 USP ;水性媒劑如(但不限於):氯化鈉注射液、林格氏 (Ringerf s)注射液、右旋糖注射液、右旋糖與氯化鈉注射液、 與加乳酸之林格氏注射液;與水互溶之媒劑如(但不限 於):乙醇、聚乙二醇與聚丙二醇;與非水性媒劑如(但不 限於):玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉 豆蔻酸異丙酯與苯甲酸苯甲基酯。 本發明非經腸式劑型中亦可添加可提高一種或多種活性 劑溶解度之化合物。例如:環糊精與其衍生物可用於提高 選擇性細胞激素抑制性藥劑與其衍生物之溶解度。參見例 如:美國專利案號5,134,127,其揭示内容已以引用之方式完 全併入本文中。 局部與黏膜劑型 本發明之局部與黏膜劑型包括(但不限於):眼藥水、噴 液、氣霧劑、溶液、乳液、懸浮液或習此相關技藝之人士 已知之其他型式。參見例如:Remington’s Pharmaceutical Sciences, 16化與 18th eds·,Mack Publishing,Easton PA (1980 & 1990);與 Introduction to Pharmaceutical Dosage Forms,4th ed·,Lea & Febiger,Philadelphia (1985)。適合治療口腔内黏膜組織之 劑型可調配成漱口水或口服凝膠。 合適之賦形劑(例如:載劑與稀釋劑)與其他可用於形成 本發明所涵括之局部與黏膜劑型之物質係習此醫藥技藝之 -52- 89179 200418455 人士已知者’且依將施用指定醫藥組合物或劑型之特定组 織而定。典型賦形劑實例包括(但不限於 乳 液或凝膠之無毒性且醫藥上可接受之 风令從礼 一 ^ 受又又尺丙酮、乙醇、乙 一醇、丙二醇、丁烷4,3_二醇、肉 田 Π二越鉍井丙酯、棕櫚酸 兴丙酯、礦物油與其混合物。若需要時, ,,了研可添加濕化劑 或保濕劑至醫藥組合物與劑型中。此签 d 土 τ 此寺其他成分實例係習 此相關技藝之人士已知者。I見例如:Remingt〇n,s… ~ M has just been used to control drug delivery methods or delivery devices known to those who are not familiar with them.丨 Examples include (but are limited to): they were stated in US patent case numbers: 3,845,770; 3,916,899; 3,536,8〇9: = ^ and 4 Ze, 719, 5,674,533, 5 () 59,595, 5,591,767-^ ' 548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, which is equal to the valley, and it is used! The formula is fully incorporated herein. These dosage forms can be used in membranes, osmotic systems, multilayer coatings, and microparticles; 1 masterbatches, gels, and samarium combinations' are used to provide slow-release or controlled-release microspheres for different proportions of desired release patterns. A variety of active agents' appropriate controlled release formulations (including those in this head _ related technology known to choose active agents to choose and use. The present invention therefore contains: =) can easily be combined with "including controlled release Single unit dosage forms suitable for oral administration 89179 -50 · 200418455 such as capsules (gelcaps) and film-coated tablets. (But not limited to) bonding agent capsules, gelatin All controlled release pharmaceutical products have an uncontrolled release equivalent The effect of the drug is its controlled release system, which is optimally designed: therapies include prolonged drug activity, reduced dosing frequency, and improved patient suitability. = Package, system, and the formulation can be used for the initiation of shadow application Or other characteristics, 'Mouth. Musical "blood concentration, which can affect the use of side effects." Xiaogentian 丨 the design of most controlled release formulations for the first release-sex boat, promote the production of required Continuous release gradually after therapeutic effect 1: Other (the amount of the tongue's pleasure 'to maintain this therapeutic or preventive effective amount of the drug-for a period of time. In order to maintain the μ amount of this drug in the body, the rate of drug release in the dosage form must be Replacement drugs in vivo And the rate of excretion. The controlled release of the active agent can be stimulated by a variety of conditions, including (but not limited to): ρΗ, temperature, enzymes, water or other physiological conditions or compounds. It is administered to patients in many different ways, including (but not limited to) · intravitreal, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial. Because its administration method mainly bypasses the patient's natural defense against foreign objects System, parenteral dosage forms are preferably sterile or can be sterilized before administration to patients. Examples of parenteral dosage forms include (but are not limited to) · ready-to-use solutions for injection, ready-to-use for dissolution or suspension in Pharmaceutically acceptable 89179 -51- 200418455 Dry products for injection vehicles, ready-to-use injectable suspensions, and emulsions. Suitable vehicles for providing parenteral dosage forms of the present invention are those skilled in the art. Examples include (but not limited to): USP for injection; aqueous vehicles such as (but not limited to): sodium chloride injection, Ringerf's injection, Dextrose injection, dextrose and sodium chloride injection, and Ringer's injection with lactic acid; vehicles that are miscible with water such as (but not limited to): ethanol, polyethylene glycol, and polypropylene glycol; and Non-aqueous vehicles such as (but not limited to): corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. It can also be used in parenteral dosage forms of the present invention. Add compounds that increase the solubility of one or more active agents. For example, cyclodextrin and its derivatives can be used to increase the solubility of selective cytokine inhibitory agents and their derivatives. See, for example, U.S. Patent No. 5,134,127, which The disclosure is fully incorporated herein by reference. Topical and mucosal dosage forms The topical and mucosal dosage forms of the present invention include (but are not limited to): eye drops, sprays, aerosols, solutions, emulsions, suspensions, or habitually Other types known to those skilled in the art. See, for example: Remington's Pharmaceutical Sciences, 16A and 18th eds, Mack Publishing, Easton PA (1980 &1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed, Lea & Febiger, Philadelphia (1985). Formulations suitable for treating oral mucosal tissues can be formulated into mouthwash or oral gel. Suitable excipients (eg, carriers and diluents) and other substances that can be used to form the topical and mucosal dosage forms encompassed by the present invention are those known to those skilled in the art -52- 89179 200418455 and will Depending on the particular tissue to which a given pharmaceutical composition or dosage form is administered. Examples of typical excipients include (but are not limited to, non-toxic emulsions or gels that are non-toxic and pharmaceutically acceptable. Receptive acetone, ethanol, ethylene glycol, propylene glycol, butane 4,3-diol , Butan Ⅱ Nikoshi Bismuth propyl ester, Xing propyl palmitate, mineral oil and mixtures thereof. If necessary, we can add wetting agents or humectants to pharmaceutical compositions and dosage forms. This sign d soil τ Examples of other components of this temple are known to those who are familiar with this technology. I see, for example: Remingt〇n, s
Pharmaceut1Cal Sciences, 16^ l8- eds., Mack Publishing, Easton PA (1980 & 1990)。 、亦可調整醫藥組合物或劑型之pH,以改善一種或多種成 分之:專送性。同樣地,可調整溶劑載劑之極性、其離子強 度或等張性,&改善傳送性。亦可添加如:硬脂酸鹽之化 合物至I藥組合物或劑型中,有利於改變—種或多種活性 劑之親水性或親脂性,U改善傳送性。此時,硬脂酸鹽可 作1調配物之脂質媒劑、乳化劑或界面活性劑及作為加上 加強傳运劑或加強滲透劑。可使用不同鹽類、水合物或溶 劑化物進一步調整所製成組合物之性質。 套組 /、土也本發明活性劑最好不同時投藥或最好不依相同 途H又藥。因此本發明涵括之套組當由醫事人員操作時, 可簡化適量活性劑投予患者之過程。 本發明 < 典型套組包括選擇性細胞激素抑制性藥劑或其 醫藥上可接受之鹽類、溶劑化物、水合物、立體異構物、 ㈤藥或籠形包合物之劑型。本發明之套組可進一步包含一 89179 -53- 200418455 種或多種其他活性劑或其組合。其他活性劑之實例已揭示 於本文中(參見例如:第4.2節)。 —本發明之套組可進一步包含用於投予活性劑之裝置。此 等裝置實例包括(但不限於)針筒、滴藥袋、貼藥與吸入器。 本發明之套組可進一步包含適用於檢測或診斷md之安斯 樂網格(Amsler grid)。 本發明之套組可進-步包含可用於投種或多種活性 劑之醫藥上可接受之媒劑。例如:若活性劑呈固體型式時, 必需再組成供非經腸式投藥用,套組可包括含合適媒劑之 密封容器,其中活性劑可溶解形成適合非經腸式投藥之無 顆粒無菌溶液。醫藥上可接受之媒劑實例包括(但不限 於广注射用水um媒劑如(但不限於):氯化納注射 液、林格氏(Ringer,s)注射液、右旋糖注射液、右旋糖與氯 化釣注射液、與加乳酸之林格氏注射液;與水互溶之媒劑 如(但不限於):乙醇、聚r — 乙一鮮與聚丙二醇;與非水性媒 劑如(但不限於):玉米油、棉籽油、花生油、芝麻油、油 鉍乙酯、肉且蔻酸異丙酯與苯甲酸苯甲基酯。 實例 下列實例係進一步說明 活體外藥學分析法 但未限制本發明範圍。 選擇性細胞激素抑制 _ &、 …〜 理王籾效應為減少合 TNF-oc。特足之選擇性細胞Pharmaceut1 Cal Sciences, 16 ^ 18-eds., Mack Publishing, Easton PA (1980 & 1990). It is also possible to adjust the pH of the pharmaceutical composition or dosage form to improve one or more of the ingredients: specific delivery. Similarly, the polarity of the solvent carrier, its ionic strength, or isotonicity can be adjusted to & improve transportability. It is also possible to add compounds such as stearates to the pharmaceutical composition or dosage form, which is beneficial to change the hydrophilicity or lipophilicity of one or more active agents, and to improve the transportability. In this case, stearates can be used as a lipid vehicle, emulsifier or surfactant for the formulation and as a transport enhancer or penetration enhancer. Different salts, hydrates or solvates can be used to further adjust the properties of the resulting composition. The kits and the active agents of the present invention are preferably not administered at the same time or are preferably not administered in the same way. Therefore, when the kit covered by the present invention is operated by medical personnel, the process of administering an appropriate amount of active agent to a patient can be simplified. The present invention < typical kit includes a dosage form of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, peony or clathrate. The kit of the present invention may further comprise 89179-53-200418455 or more other active agents or a combination thereof. Examples of other active agents have been disclosed herein (see, e.g., Section 4.2). -The kit of the present invention may further include a device for administering the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches and inhalers. The kit of the present invention may further include an Amsler grid suitable for detecting or diagnosing MD. The kit of the present invention can further comprise a pharmaceutically acceptable vehicle that can be used for seeding or multiple active agents. For example, if the active agent is in a solid form, it must be reconstituted for parenteral administration. The kit may include a sealed container containing a suitable vehicle, wherein the active agent can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. . Examples of pharmaceutically acceptable vehicles include (but not limited to, um vehicles for water injection such as (but not limited to): sodium chloride injection, Ringer's (Ringer's) injection, dextrose injection, right Rotary sugar, chlorinated fishing injection, and Ringer's injection with lactic acid; vehicles that are miscible with water such as (but not limited to): ethanol, poly-r-ethylene glycol and polypropylene glycol; and non-aqueous vehicles such as ( (But not limited to): corn oil, cottonseed oil, peanut oil, sesame oil, bismuth ethyl oil, isopropyl myristate and benzyl benzoate. Examples The following examples further illustrate the in vitro pharmaceutical analysis method without limiting the present. The scope of the invention. Selective cytokine inhibition_ &…; Li Wang's effect is to reduce TNF-oc. Special selective cells
敫素抑制性藥劑可加強TNF mRNAP李解。TNF-α可能在龙 ―、 此在只斑變性中扮演某種病理角色 明確之具體實施例中,於活两曲 万、,舌體外試驗中探討3-(3,4-二甲. 89179 -54- 200418455 基-苯基)_3·( 1-氧代氫_異蚓哚士基)丙醯胺之藥理性 質。孩試驗測足該化合物對多種細胞激素之生產之影響。 於活體外探討化合物抑制Lps所刺激人類pBMC與人類全血 產生TNF-α《效果。活體外試驗顯示,3_(3,4_二甲氧基·苯 基)-3-(1-氧代-1,3-二氫_異…哚冬基)_丙醯胺之藥理活性圖 形比沙利竇邁強5至5〇倍。3_(3,4_二甲氧基-苯基Η仆氧代 -1,3-二氫-異吲哚-2-基)_丙醯胺之藥效可能衍生自其抑制發 炎細胞激素產生之作用。 MD患者之臨床讀 育斑’k性患者之選擇性細胞激素抑制性藥劑投藥量為每 天約20至約1200 mg。明確具體實施例中,臨床試驗係由4〇 位黃斑變性患者,分成兩組進行。第一組接受傳統上使用 菲特芬之光動力學療法封閉滲漏之脈絡膜血管(此疾病之 特徵)之治療法。Ophthalmol 1999 (117) : 1329-1345。第二組 接受使用菲特芬之相同傳統療法與約2〇 mg/天之( + )-241(3-乙氧基-4·甲氧基苯基)-2-甲基續醯基乙基]乙醯基胺基異 吲哚啉_1,3·二酮作為輔劑,共2〇週。 接受(+ )-2-[ 1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺醯基乙 基]-4_乙醯基胺基異⑼哚啉二酮之試驗組充分遏止一 連串之新生血管反應,無限期延長光動力學療法之效果。 然而,未使用(+)-2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺醯 基乙基]-4-乙醯基胺基異吲哚啉-i,3-二酮之第一組則在處 理後數週,經處理之血管卻出現再滲流之現象。隨後即逐 漸喪失視力,需要重覆光動力學療法。 其他較佳具體實施例中,(+ )-2-[1-(3-乙氧基-4-甲氧基苯 89179 -55- 200418455 基)-2-甲基磺醯基乙基]-4-乙醯基胺基異β哚啉-1,3-二難I之 投藥量為約1至約200 mg/天,較佳約10至約50 mg/天,或更 兩劑量,通常為每隔一天使用每日劑量之約1.5至2.5倍。輔 助療法適用於其他用於治療或預防MD之傳統療法,包括 (不、人 本、:手術干預法,包括雷射光致凝結法。 本文發明具體實施例僅供說明本發明之範圍。 本之中。,又獻之揭示内纟已以引用之方式完全併入 89179 56-The hormonal inhibitory agent can enhance the TNF mRNA P Liye. TNF-α may play an important role in the pathogenesis of plaque degeneration only in dragons. In this specific example, it is discussed in the in vitro test of 3- (3,4-dimethylamino) in vitro. 89179- Pharmacological properties of 54-200418455-phenyl-phenyl) -3. (1-oxohydro-isoeardodolyl) propanamide. The child test measures the effects of this compound on the production of various cytokines. The effect of compounds in inhibiting the production of TNF-α by human pBMC and human whole blood stimulated by Lps was investigated in vitro. In vitro tests show that the pharmacological activity of 3_ (3,4_dimethoxy · phenyl) -3- (1-oxo-1,3-dihydro_iso ... dodonyl) _propanamide is bisal Ricci is 5 to 50 times stronger. The effect of 3_ (3,4_dimethoxy-phenylpyridineoxo-1,3-dihydro-isoindol-2-yl) _propanamide may be derived from its inhibition of inflammatory hormone production effect. The clinical reading of MD patients with plaque'k patients has a selective cytokine inhibitory dosage of about 20 to about 1200 mg per day. In a specific embodiment, the clinical trial is performed by 40 patients with macular degeneration divided into two groups. The first group received treatments that traditionally used Fettenven's photodynamic therapy to seal leaky choroidal vessels (a characteristic of this disease). Ophthalmol 1999 (117): 1329-1345. The second group received the same traditional therapies with Fettphene and about 20 mg / day of (+)-241 (3-ethoxy-4 · methoxyphenyl) -2-methylcontinylethyl ] Acetylaminoisoindolinoline 1,3 · dione as adjuvant for 20 weeks. Accept (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4_ethylamidoaminoisoxolinolinone The experimental group fully suppressed a series of neovascular reactions and prolonged the effect of photodynamic therapy indefinitely. However, (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetamidoaminoisoindole was not used In the first group of phthaloline-i, 3-dione, re-perfusion occurred in the treated blood vessels several weeks after the treatment. He gradually lost vision and needed to repeat photodynamic therapy. In other preferred embodiments, (+)-2- [1- (3-ethoxy-4-methoxybenzene 89179 -55- 200418455) -2-methylsulfonylethyl] -4 -The dosage of ethanoylaminoiso-β-doline-1,3-diazepine I is about 1 to about 200 mg / day, preferably about 10 to about 50 mg / day, or two doses, usually per Use about 1.5 to 2.5 times the daily dose every other day. Adjuvant therapy is applicable to other traditional therapies for the treatment or prevention of MD, including (no, human, and: surgical intervention methods, including laser-induced coagulation. The specific embodiments of the present invention are only for illustrating the scope of the present invention. ..., and it is revealed that the inner concubine has been fully incorporated by reference into 89179 56-
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US7776907B2 (en) * | 2002-10-31 | 2010-08-17 | Celgene Corporation | Methods for the treatment and management of macular degeneration using cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindoline-4-yl}carboxamide |
MX347928B (en) * | 2011-01-10 | 2017-05-19 | Celgene Corp | Phenethylsulfone isoindoline derivatives as inhibitors of pde 4 and/or cytokines. |
KR101908330B1 (en) | 2017-02-17 | 2018-10-16 | 인제대학교 산학협력단 | Novel anti-vascular endothelial growth factor antibody and composition for preventing or treating age-related macular degeneration comprising thereof |
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ES2975968T3 (en) * | 2018-12-03 | 2024-07-18 | Smilebiotek Zhuhai Ltd | Octyl gallate and esters thereof for use in the treatment and prevention of age-related macular degeneration caused by Bacillus Megaterium |
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